### DEPARTMENT OF HEALTH AND HUMAN SERVICES

# CENTERS FOR DISEASE CONTROL AND PREVENTION

## Advisory Committee on Immunization Practices

## October 24-25, 2007

**Atlanta, Georgia**

**Record of the Proceedings**

**[TABLE OF CONTENTS]{.mark}**

[]{.mark}

**[Welcome & Introductions]{.mark}**

[]{.mark}

**[Influenza Vaccines]{.mark}**

> [Overview of Session and Influenza Vaccine Update]{.mark}
>
> [Use of Live Attenuated Influenza Vaccine in 25-59-month-old
> Children]{.mark}
>
> [Summary of CDC-CSTE Consultants Meeting; Influenza Vaccine
> Recommendations for 5-18-year-olds]{.mark}
>
> [Federal Interagency Working Group: Draft Guidance on Pandemic Vaccine
> Prioritization]{.mark}
>
> [Cost-effectiveness of Influenza Vaccination: Updated Estimates for
> Children Aged 2-4 years]{.mark}
>
> []{.mark}

**[Pediatric Use of Pneumococcal Vaccines]{.mark}**

> [Use of Pneumococcal Conjugate Vaccine (PCV7) in 24-59-month-old
> Children Who Are Incompletely Vaccinated]{.mark}
>
> []{.mark}

**[Meningococcal Conjugate Vaccine (MCV4)]{.mark}**

> [Introduction]{.mark}
>
> [Update: Meningococcal Vaccine Safety]{.mark}
>
> [Immunogenicity and Safety of Menactra (MCV4) in 2-10-year-old
> Children9]{.mark}
>
> [Proposed Recommendations for Use of MCV4 in 2-10-year-old Children at
> Increased Risk of Meningococcal Disease]{.mark}
>
> [Considerations for Routine Use of MCV4 in 2-10-year-old
> Children]{.mark}
>
> []{.mark}

**[Childhood and Adolescent Immunization Schedule]{.mark}**

[]{.mark}

**[Combination Vaccines]{.mark}**

> [Update: Combination Vaccines Working Group]{.mark}
>
> [Impact of Combination Vaccines]{.mark}
>
> [Immunogenicity and Safety of Kinrix in Children 4-6 Years of
> Age]{.mark}
>
> []{.mark}

[**Immunization Schedule for HIV-Infected Adults**8]{.mark}

[]{.mark}

[**Vaccine Supply**3]{.mark}

[]{.mark}

**[Public Comment]{.mark}**

[]{.mark}

**[Human Papillomavirus (HPV) Vaccines]{.mark}**

> [Introduction]{.mark}
>
> [Overview of HPV Vaccine Trial Data]{.mark}
>
> [Quadrivalent HPV Vaccine Cross-Protection]{.mark}
>
> [Bivalent HPV Vaccine ASO4 Adjuvant System]{.mark}
>
> [Bivalent HPV Vaccine Clinical Overview and Safety Review]{.mark}
>
> [Outcomes Related to HPV 6/11: Recurrent Respiratory Papillomatosis
> and Genital Warts]{.mark}
>
> [Issues for ACIP Consideration]{.mark}
>
> []{.mark}

**[Immunization Safety]{.mark}**

> [Introduction]{.mark}
>
> [Early Thimerosal Exposure and Neuropsychological Outcomes at 7-10
> Years]{.mark}
>
> [Summary of Syncope Reports to VAERS, January 2005 -- July
> 2007]{.mark}
>
> [Update: Varicella Vaccine Safety 1995-2005]{.mark}
>
> []{.mark}

**[Rotavirus Vaccines]{.mark}**

> [Working Group Update]{.mark}
>
> [GSK's Human Rotavirus Vaccine Rotarix]{.mark}
>
> [PRV (Rotateq) Update]{.mark}
>
> []{.mark}

**[Update: Hepatitis B]{.mark}**

> [Hepatitis B Vaccination of Adults]{.mark}
>
> [Identification and Public Health Management of Persons Chronically
> Infected with Hepatitis B Virus]{.mark}
>
> []{.mark}

**[Agency Updates]{.mark}**

[]{.mark}

**[Public Comment]{.mark}**

**[List of Members and Other Participants]{.mark}**

[]{.mark}

**[List of Acronyms]{.mark}**

**Minutes of the Meetin[g]{.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) convened a meeting of the Advisory
Committee on Immunization Practices (ACIP). The meeting was held on
October 24-25, 2007 at CDC's Global Communications Center in Atlanta,
Georgia

**[Welcome and Introductions]{.mark}**

**Dr. Tanja Popovic, Chief Science Officer, CDC**

**[Dr. Dale Morse, Chair, ACIP]{.mark}**

**[Dr. Larry Pickering, Executive Secretary, ACIP/CDC]{.mark}**

[]{.mark}

[Dr. Popovic welcomed committee members and attendees on behalf of Dr.
Gerberding and the CDC. She noted that the ACIP has been in existence
for over 40 years and its work has contributed to CDC's being an agency
highly trusted both in this country and globally. Science is the
cornerstone of what CDC and this committee do and prevention is CDC's
overall focus. Prevention requires that the science and evidence base be
translated into practice, which unfortunately often takes years.
Measurable impact is another CDC focus. This work of this committee is
highly visible and members help CDC make difficult decisions and give
people what they need as quickly as possible. As such, they bring
enormous credibility to the work of the committee and to CDC as a whole.
Finally, committee members are people of high integrity who are able to
work on sensitive issues in an open manner, for which much praise and
appreciation are due.]{.mark}

[Dr. Popovic introduced the new ACIP chair, Dr. Dale L. Morse, who has
served as an ACIP member since 2005. He is the director of the Office of
Science and Public Health at the New York State Department of Health.
New members to the ACIP include Dr. Lance Chilton, Professor, Department
of Pediatrics, University of New Mexico School of Medicine; Dr. Paul
Cieslak, Medical Director, Immunization Program, Program Manager, Acute
and Communicable Disease Program, Oregon Public Health;]{.mark} Dr.
[Allen Craig, State Epidemiologist, Director, Communicable and
Environmental Disease Services, Tennessee Department of Health; Dr.
Janet Englund, Associate Professor of Pediatrics, University of
Washington, Fred Hutchinson Cancer Research Center, Children\'s Hospital
and Regional Medical Center, Seattle, Washington; and Dr. Franklyn
Judson, Professor, Departments of Medicine and Preventive Medicine and
Biometrics, University of Colorado at Denver and Health Science
Center.]{.mark}

[New liaison organizations include: the American Osteopathic
Association, represented by Dr. Stanley Grogg; the Society of Healthcare
Epidemiology of America, represented by Dr. Harry Keyserling; the
American Geriatrics Society, represented by Kenneth Schmader; and the
National Association of Pediatric Nurse Practitioners, for which a
representative will be selected in 2008.]{.mark}

[Two high-profile groups visiting the ACIP meeting were recognized. The
first was a delegation from Japan, led by Dr. Koichi Yamanishi, Director
General of the National Institute of Biomedical Innovation in Tokyo,
Japan. He and his colleagues are establishing an advisory committee on
immunization practices in Japan. The People\'s Republic of China
national and provincial health officials were attending a two-week CDC
course on vaccine-preventable diseases. The delegation was led by Dr.
Xin-Sheng Gong, the Director of the Expanded Program on Immunization
Division of the China Centers for Disease Control and Prevention,
Ministry of Health, Beijing, China.]{.mark}

[Dr. Pickering introduced Tonica Gleaton, the new ACIP program analyst.
He noted that Dr. George Curlin from NIH was unable to attend, but Dr.
Carolyn Deal will attend in his place. Dr. Norm Baylor from the FDA was
also unable to attend, but Florence Houn was there on his
behalf.]{.mark}

[The ACIP charter gives the executive secretary or his or her designee
the authority to temporarily designate an ex-officio member as a voting
member if there are fewer than eight appointed members available or
qualified to vote due to a financial conflict of interest. Their
conflicts of interest, if any, will be sought before any votes are
taken. Topics presented at the ACIP meeting include open discussion with
time reserved for public comment. To ensure transparency, CDC encourages
people to advise the committee of any financial relationships that are
likely to be impacted by the topic being discussed.]{.mark}

[The goal in appointing members to the ACIP is to achieve the greatest
level of expertise while minimizing potential for actual or perceived
conflicts of interest. Members of the ACIP agree to forgo participation
in certain activities related to vaccines during their tenure on the
committee. For certain other interests that potentially enhance a
member\'s expertise, the CDC has issued limited conflict of interest
waivers. Members who conduct clinical vaccine trials or serve on data
safety monitoring boards may serve as consultants on matters related to
those vaccines, but they are prohibited from participating in
deliberations or votes of the committee on issues related to those
specific vaccines. Regarding other vaccines of the affected company, a
member may participate in discussion with the proviso that he or she
abstains from voting related to the vaccines of that company.]{.mark}

[Dr. Morse welcomed all U.S. and international guests, the new members,
and liaisons. He particularly welcomed participation of the American
Geriatrics Society because it reflects the expanded focus on adult
preventive vaccines. ACIP recently has been involved with a number of
vaccines for adults, including Tdap, pneumococcal, influenza, and
zoster. The potential for adjuvants is good news for the aging baby
boomer population. He then called for statements on conflicts of
interests of committee members.]{.mark}

[Dr. Morse: no conflicts.]{.mark}

[Dr. Baker: no conflicts.]{.mark}

[Dr. Chilton: no conflicts.]{.mark}

[Mr. Beck: no conflicts.]{.mark}

[Dr. Cieslak: no conflicts.]{.mark}

[Ms. Stinchfield: no conflicts.]{.mark}

[Dr. Lett: no conflicts.]{.mark}

[Dr. Hull: I\'ve had some discussions with MedImmune about a project
that could become a conflict. I\'ve also been approached by a recruiter
from sanofi, and so I will not be voting vaccines manufactured by those
two companies.]{.mark}

[Dr. Englund:]{.mark} I get research support from MedImmune for clinical
studies, including FluMist in children with cancer.

[Dr. Morita: no conflicts.]{.mark}

[Dr. Craig: no conflicts.]{.mark}

[Dr. Lieu: I receive government funding from CDC and NIH for studies of
vaccine economics and safety, and I have no conflicts.]{.mark}

[Dr. Judson: no conflicts.]{.mark}

[Dr. Neuzil: no conflicts.]{.mark}

Dr. Sumaya: no conflicts.

**Influenza Vaccines**

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

**[Dr, Greg Wallace, CDC/NCIRD/ISD]{.mark}**

**[Dr. Kathleen Neuzil, ACIP WG Chair]{.mark}**

**[Dr. Lisa Prosser, Harvard Medical School]{.mark}**

**[Dr. Benjamin Schwartz, CDC/NVPO]{.mark}**

[]{.mark}

**[Influenza Vaccine Update]{.mark}**

[]{.mark}

[After outlining the session, Dr. Fiore presented current ACIP
recommendations for influenza vaccine. Those published in the *MMWR* in
2007 include every underlying condition that might give an indication
for influenza vaccine. A simpler version is to vaccinate persons at high
risk of complications, their contacts and those who care for them, plus
anyone who wants to be vaccinated.]{.mark}

[Before 2000, annual vaccination was recommended for persons 65 and
older, persons with chronic underlying medical conditions, pregnant
women in their second or third trimester, contacts of any in the first
three groups, and healthcare workers. In 2000, the recommendations were
extended to all adults ages 50 and older because many had chronic
underlying conditions. In 2004, all children ages 6 to 23 months were
recommended for annual vaccination and as well as their contacts and
out-of-home caregivers. The recommendation for pregnant women was
advanced to include all women who will be pregnant during the influenza
season. In 2006, all children between 6 and 59 months as well as their
out-of-home caregivers and their close contacts were added.]{.mark}

[Data from the National Health Interview Survey for different adult age
groups indicate that by 2006, for adults 65 and older, vaccination
coverage of between 60 and 70 percent had been achieved, reaching a
plateau of around 70 percent. Coverage of 50- to 64-year-olds, who are
at higher risk of influenza complications, has not substantially
increased in recent years, reaching a plateau of about 40 to 50 percent.
Healthy adults in that age group, who also are recommended for
vaccination, are at about 30 percent. Younger adults at higher risk for
influenza complications are also at lower coverage levels. Healthcare
workers are between 35 and 40 percent coverage annually and pregnant
women have not yet reached 20 percent coverage.]{.mark}

[Vaccination of 6- to 23-month-olds is a high priority because their
rates of hospitalization for influenza are similar to those observed in
the elderly. They require two doses if it is their first year of
vaccination. In the past two years, 33 and 32 percent one-dose coverage
has been achieved. For two doses, coverage last year was 21 percent.
More recent data are available from immunization information systems or
registries, including coverage from the last influenza season. For the
6- to 23-month-olds, overall coverage for both one and two doses has not
substantially increased over the last three years. For 2006-2007, 6 to
22 percent of 24- to 59-month-olds had received at least one dose and
between 2 and 18 percent had been fully vaccinated.]{.mark}

[]{.mark}

**[Use of Live Attenuated Influenza Vaccine in 25-59 Month Old
Children]{.mark}**

[]{.mark}

[In 2006, MedImmune submitted a supplement to their Biologic License
Application, or BLA, to allow use of FluMist in 12- to 59-month-olds.
Their primary data source was the CP111 study, which was presented to
ACIP in detail in October 2006, and safety data were presented in
February 2007. A study by Belshe *et al.* was published in the *New
England Journal* in February 2007. This was a large study with about
8,000 subjects, a double-blind, randomized trial with an active control.
The active control was inactivated influenza vaccine and included
pre-specified analyses for the 6- to 23-month-olds and 24- to
59-month-olds. Exclusion criteria included children with medically
diagnosed or treated wheezing within 42 days before enrollment or a
history of severe asthma as judged by the investigator. However, many
other children with a history of mild or moderate asthma or history of
wheezing more than 42 days before enrollment were included in the
trial.]{.mark}

[The FDA and MedImmune discussed this application at a VRBPAC meeting in
May 2007 and the FDA concluded that FluMist was safe and effective in
subjects 24 months of age and older. However, among subjects less than
24 months of age, the participants who received FluMist had increased
hospitalizations, severity of wheezing, and severity of respiratory
events, according to the FDA analyses. The number of these adverse
events was quite small and the large majority of instances of medically
significant wheezing, for example, required no more than a short course
of a bronchodilator and a medical evaluation. But there was a
statistically significant increase in these wheezing end points compared
to children who received TIV.]{.mark}

[In May 2007, the FDA issued a warning letter to MedImmune for unrelated
manufacturing concerns, and the BLA supplement decision was delayed, as
well as the planned vote at the June 2007 meeting. By September, the
issues had been resolved, and the BLA supplement application was
approved, but it differed from the original request. FluMist was
indicated for persons 2- to 49-years-old, but providers were advised to
avoid administering FluMist to children less than 24 months old,
individuals with asthma, and children less than five years of age with
recurrent wheezing. Safety was not established in persons with
underlying medical conditions predisposing them to wild-type influenza
infection complications. Parents or guardians were to be asked if the
vaccinee had asthma or, for children less than five years old, recurrent
wheezing, since this may be an asthma equivalent in this age
group.]{.mark}

[The influenza vaccine working group concluded that LAIV efficacy was at
least equivalent to TIV efficacy for children six months and older. In
the clinical trial, LAIV had a 55 percent greater relative efficacy
compared to TIV. There was also good evidence for safety among healthy
children 24 months and older without a history of asthma or wheezing.
However, additional information on safety is needed for children more
than 24 months old with a history of asthma or wheezing. Safety
monitoring of FluMist use in young children will use the current
reporting systems: the Vaccine Adverse Events Reporting System, or
VAERS, and the Vaccine Safety Datalink.]{.mark}

[The work group concluded that a better definition of recurrent wheezing
was needed and that the ACIP should provide more guidance about which
two- to four-year-olds were candidates for getting FluMist and which
might be better off getting TIV because of the potential for
post-vaccination wheezing after FluMist. Asking about recurrent wheezing
would not exclude some children who were excluded from the study, such
as those with a single, recent wheezing episode. Young children who are
predisposed to reactive airways diseases might not be old enough to have
had more than one episode of wheezing. A single simple question
consistent with guidance from other organizations was most likely to be
understood and used.]{.mark}

[The working group suggested the following guidance: FluMist is not
recommended for use in children with underlying medical conditions,
including asthma, that predispose them to influenza complications.
However, some two- to four-year-old children have a history of wheezing
and respiratory illnesses but have not been diagnosed with asthma.
Therefore, to identify children who might be at higher risk for asthma,
persons administering FluMist should ask parents and guardians of 24- to
59-months-olds the following question: In the past 12 months, has a
healthcare provider ever told you that your child had wheezing or
asthma? LAIV, or FluMist, is not recommended for children whose parents
answer yes to this question or for children with a wheezing episode
noted in the medical record within the past 12 months. This guidance was
developed in collaboration with representatives from the Committee on
Infectious Diseases of the American Academy of Pediatrics and additional
guidance might be considered as more post-marketing safety data are
available.]{.mark}

[The work group will continue to follow LAIV issues, including the use
of LAIV for children with a history of wheezing and optimal vaccination
strategies for use of LAIV and TIV in young children. As LAIV safety
analyses from VAERS, VSD, and the various post-licensure studies become
available, the work group will consider them as well. It proposes that
LAIV be recommended for use in two- to four-years-olds and that either
TIV or LAIV can be used for healthy persons aged 2 to 49 years, i.e.,
persons who do not have an underlying medical condition that predisposes
them to influenza complications.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Morse asked whether it had been possible to take the definition of
wheezing and analyze the clinical trials to see how many children might
have answered that case definition. Dr. Fiore replied that the current
definition was more restricted than the one used in the clinical trial,
which involved exclusion for severe asthma. As far as children who had
wheezing in the past but were enrolled in the trial, he had no
information about who might have not gotten FluMist. Dr. Neuzil noted
that the fact that the current definition of wheezing is slightly more
conservative than what was used in the clinical trials was partly an
effort to simplify the question asked in a clinical practice.]{.mark}

[Dr. Cieslak wondered if anyone had tested the predictive value of
asking parents this question and what sort of language was used. Dr.
Fiore acknowledged that the predictive value was unknown. The question
would be directed to the parents, based on what a healthcare provider
had told them, since the medical record might not be available.]{.mark}

[Dr. Whitley-Williams, National Medical Association, noted that in the
Belshe trial there were only 300 African-Americans out of over 8,000
participants. She was concerned about recommending live vaccines for
children between 2 and 59 months, a population susceptible to asthma and
reactive airway disease or wheezing, particularly in inner cities. She
asked if there was any additional information on the side effects of
wheezing in this population, and added that there were also very low
numbers of Asians and Hispanics. Dr. Fiore said he had no additional
information about minorities, but that there was an alternative
influenza vaccine in clinics with high rates of asthma and reactive
airways diseases.]{.mark}

[Dr. Lewis noted that pediatricians consider recurrent wheezing to be at
least more than one episode and asked whether any episode of wheezing
with an acute illness would then be a contraindication. Dr. Fiore
replied that it would be, if it had occurred in the last 12 months. The
reason for the 12-month time period was to avoid excluding three-year
olds who had an episode of wheezing associated with a respiratory
infection when they were nine months old, for example, but had not had
wheezing since.]{.mark}

[Dr. Salisbury, Department of Health, London, commented that clinical
trials often exclude the very children for whom answers and protection
are most needed, such as children with epilepsy. He asked what the
process would be for answering questions about vaccinating children with
medical conditions that put them at higher risk for influenza if they
are excluded from trials. Dr. Fiore replied that the FDA indication
states that safety has not been shown in those children. Dr. Englund,
who had received support to study this vaccine in the recent past, added
that other large studies allowed children with all kinds of underlying
medical conditions, except for recurrent wheezing. Dr. Neuzil responded
that there was an alternative vaccine and that a conservative approach
was being taken until more information through postmarketing
surveillance or other means was available. The work group has identified
this group of children as a priority, along with adults 50 or more years
of age and adults with other medical conditions.]{.mark}

[Dr. Temte stated that there would probably be no problem with children
seen in a medical setting. For children showing up for a standing-order
type immunization, the language about the wheezing episode or asthma
seems simple and elegant and would be supported by the AAFP.]{.mark}

[Dr. Walker, MedImmune, responded to the question about race or
ethnicity. The FluMist database has about 14,000 children between 24 to
59 months of age and approximately 6 percent are black. In multiple
subset analyses, no age, gender, or race/ethnicity differences have been
seen in terms of safety events, including wheezing. The label language
negotiated with the FDA was not based on a safety signal in children
with asthma, but was an effort to harmonize the label with the fact that
FluMist was not felt to have been sufficiently studied in adults or
children with asthma. In fact, in the head-to-head trial, FluMist versus
TIV, in children 24 to 59 months of age, rates of wheezing and
hospitalizations were lower in FluMist, though the difference was not
statistically significant. In the subset of children who had wheezing
within the past year, which is about 13 percent of the children on the
study in that age group, wheezing was numerically lower in TIV
recipients versus FluMist. So there was no evidence to suggest that
wheezing within the past 12 months was a proxy.]{.mark}

[Dr. Morse asked if the committee was ready to vote. Dr. Baker moved
approval of the recommendation that either TIV or LAIV can be used for
healthy persons aged 2 to 49 and Ms. Stinchfield seconded the
motion.]{.mark}

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

[Dr. Judson; yes.]{.mark}

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

[Dr. Craig; yes.]{.mark}

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

[Dr. Englund; abstain.]{.mark}

[Dr. Hull; abstain.]{.mark}

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

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

[Dr. Cieslak; yes.]{.mark}

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

[Dr. Chilton; yes.]{.mark}

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

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

[]{.mark}

**[VFC Vote]{.mark}**

[]{.mark}

[Dr. Wallace presented a proposal for an update of the VFC resolution
for live attenuated influenza vaccine and pointed out that what had been
done was to add the clarifying language of healthy children and expand
the age recommendation down to two years of age, with a priority when
vaccine is limited for those 2 to 59 months of age, since they are
recommended to get it as a routine. When vaccine is plentiful, any child
who is VFC eligible up to age 18 could get it. All the language about
who should not get the vaccine was moved to the contraindication. The
minimum interval between two doses has been harmonized. The LAIV
contraindications and precautions are verbatim from the FDA label
package insert.]{.mark}

[Dr. Baker asked if contraindications for both vaccines would be egg
allergies. Dr. Wallace confirmed that this was so.]{.mark}

[Dr. Baker moved approval and Ms. Stinchfield seconded the
motion.]{.mark}

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

[Dr. Chilton; yes.]{.mark}

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

[Dr. Cieslak; yes.]{.mark}

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

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

[Dr. Hull; abstain.]{.mark}

[Dr. Englund; abstain.]{.mark}

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

[Dr. Craig; yes.]{.mark}

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

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

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

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

[]{.mark}

**[Influenza Vaccine Recommendations for 5-18 Year Olds: Summary of
CDC-CSTE Consultants Meeting]{.mark}**

[]{.mark}

[Dr. Fiore showed the draft time frame for expanding recommendations and
explained that the committee was now in the first phase, which is
considering expansion to include school-aged children. Six- to
59-month-olds already have a routine annual vaccination recommendation;
2010 and 2011 is the time frame for considering expansion to contacts of
school-aged children and then in 2012 to 2013, a universal vaccination
recommendation will be considered. The discussion can be broken down
into six critical factors: vaccine supply; vaccine effectiveness;
vaccine safety; disease burden; feasibility of implementation,
especially a sustained implementation; and cost-effectiveness.]{.mark}

[In September 2007, CDC invited a diverse group of approximately 70
consultants address these issues. They included influenza researchers
and epidemiologists, public health and professional organization
representatives, community vaccinators, school health officials, vaccine
manufacturers, and safety experts. The objectives were to review the
evidence base supporting expansion of recommendations to include all
school-aged children, identify key evidence gaps, identify
implementation challenges and potential solutions, and discuss potential
methods for assessing impact.]{.mark}

[Plenary sessions included an update from the vaccine manufacturers,
vaccine safety and effectiveness issues, disease burden in school-aged
children, potential opportunities and challenges in various vaccination
settings, practical experience for immunizing children of this age and
evaluating impact, economic analyses, and perspectives from a variety of
different organizations about resources they could bring to bear on an
expansion recommendation.]{.mark}

[Regarding the influenza vaccine supply, as many as 130 million total
doses for all ages are projected over the next few seasons, with the
capacity to scale up to over 200 million doses within the next five
years. All estimates are subject to change, based upon the market, the
selected strain-growth characteristics, and regulatory
approvals.]{.mark}

[MedImmune, which makes FluMist or LAIV, reports capacity for 20 million
thimerosal-free nasal vaccine doses in 2008-2009 and 35 million doses in
2009 and 2010 or later. Thimerasol remains a barrier for some, even
though there are no studies that indicate harm from this vaccine
preservative. ACIP has not expressed a preference for thimerosal content
in influenza vaccines.]{.mark}

[Novartis, which makes Fluvirin, one of the TIV formulations, has the
capacity for 55 million doses within five years, for all age groups.
They have an increasing proportion of preservative-free, including
pediatric vaccines. Sanofi, which makes Fluzone, another TIV, has the
capacity for 100 million doses by 2009, all ages; an increasing
proportion of these are also thimerosal-free.]{.mark}

[GlaxoSmithKline, which makes Fluarix, FluLaval and other TIV vaccines,
currently has only adult formulations on the market. However, they are
planning to introduce pediatric vaccines in the next couple of years and
have the capacity for 15 to 17]{.mark} million p[reservative-free doses
for children and the potential availability of doses for 6- to
35-month-olds.]{.mark}

[CSL had a new TIV formulation approved for adults in September 2007.
The company reports approximately 2 million doses will be available this
influenza season, both a multi-dose and a preservative-free,
thimerosal-free, formulation. They plan to develop a pediatric vaccine
and capacity for 20 million doses annually within 5 years.]{.mark}

[Regarding effectiveness in school-aged children, most consultants
thought that children develop a robust antibody response to influenza
vaccine and that efficacy in this age group is good. Studies have shown
it is 50 to 90 percent effective against laboratory-confirmed influenza,
best in years when the antigenic characteristics of the circulating
viruses are similar to the vaccine strains. Several consultants noted
that yearly assessments of vaccine effectiveness would be helpful, along
with studies with statistical power to show vaccine effectiveness
against severe outcomes, such as hospitalization. Limited data indicate
that vaccine effectiveness does not decline among children immunized
over multiple years, however there are a few studies with data that
extends beyond five years of immunization.]{.mark}

[Multiple established systems monitor influenza vaccine safety in this
age group, including the Vaccine Adverse Events Reporting System
(VAERS); the Vaccine Safety Datalink (VSD), which now has rapid-cycle
analysis capacity; and the Clinical Immunization Safety Assessment
Network or CISA Network. The safety profile is expected to be good,
based on current data, among children immunized over multiple years,
however, the data are limited. There are also fairly limited safety data
for adolescents, especially for simultaneous administration with other
adolescent vaccines. Systems that capture safety data for vaccinations
given outside of medical settings will have to be developed.]{.mark}

[Regarding the burden of influenza illness among school-aged children,
severe outcomes, such as hospitalization and death, are rare. There was
a strikingly higher rate of hospitalization in 2003-2004 for the zero-
to four-year-old age group, but overall, rates are considerably lower in
5- to 17-years-old as compared to children four and younger. There have
been between 40 and 70 deaths among children reported over the past
three years, average age between four and seven.]{.mark}

[Peak influenza infection rates occur among school-aged children, most
involving several days of respiratory illness with a full recovery. Data
from a prospective study in a single school showed that the numbers of
illness episodes, school days missed, febrile illnesses, days of work
missed, and infections among household members were significantly
elevated during that influenza season as compared to other parts of the
winter respiratory virus season. Healthcare visits and antibiotic use
did not increase significantly. However, in other studies these outcome
measures increased during the influenza season compared to other parts
of the winter.]{.mark}

[Kathryn Edwards from Vanderbilt reviewed the data showing few deaths
and hospitalizations among school-aged children compared to younger
children, the elderly, or the chronically ill. However, there were five
to seven outpatient visits per 100 children annually. In many instances,
children received antibiotics, often inappropriately. There were 10 to
30 illnesses per 100 children, and they were frequently associated with
school absenteeism.]{.mark}

[Implementation questions took up a large part of the discussions ,
i.e., what would it take to deliver influenza vaccine to 50 and 55
million children between the ages 5 to 18 every year in the short time
frame available? Several consultants noted their experiences with the
current recommendations. First, approximately 50 percent of school-aged
children already have an indication, because they have a chronic
underlying illness or because they are contacts of persons at
risk.]{.mark}

[Second, there is inconsistent public interest in influenza vaccination
and the media tend to focus on rare, severe outcomes; it is difficult to
get attention for low coverage rates.]{.mark}

[Providers and programs have been relatively slow to adopt strategies
known to improve coverage, such as reminder and recall systems, enhanced
access, and reducing missed opportunities. Providers and healthcare
workers are not always advocates for influenza vaccination and do not
necessarily get vaccinated themselves. Finally, there are formidable
logistical challenges to vaccinating school-aged children. Some
providers report they are near capacity to provide influenza vaccination
just with the current recommendations.]{.mark}

[Peter Szilagyi of Rochester analyzed how school-aged recommendations
would impact visits to the medical home. He evaluated a strategy of
vaccinating school-aged children at every well-child visit or at any
clinic visit of any kind over a three-month window of time and a
five-month window of time. Most 5- to 8-year-olds would require one or
two additional visits since they had not been vaccinated in the past and
are recommended for two vaccinations in the first year. Children ages 9
to 18 visit the medical home less often, but need only one vaccination.
If all visits were used and vaccination was continued throughout a
five-month-time window, about two-thirds would require an extra medical
visit. While some are already indicated to get influenza vaccine, Dr.
Szilagyi estimated an overall increase of 68 percent more primary care
visits for 5- to 18-year-olds across the country if influenza
vaccination was begun in the medical home and high coverage were to be
achieved.]{.mark}

[School-based vaccination programs are one possibility for reducing the
burden on providers. Representatives from immunization programs and
school health groups both noted that schools and public health share a
goal of improving the lives of children, which is a basis for working
together. School administrators might be intrigued by the potential
benefits of reducing influenza, in that it could reduce absenteeism and
would help children to be ready to learn. However, most school health
infrastructures are less robust than they were 20 or 30 years ago, so
considerable outside assistance would be needed. Furthermore, since
schools are locally controlled, this would mean district by district
uptake of acceptance of setting up vaccination programs in
schools.]{.mark}

[Knox County, Tennessee has had a school-based immunization program for
the past two seasons. Most of the children received LAIV donated by
MedImmune and some additional support was also provided. Each year,
approximately 30,000 children were vaccinated in over 80 schools.
Coverage reached approximately 50 percent in both children and faculty.
This was very large and challenging undertaking but was reportedly well
received by all involved.]{.mark}

[Consultants generally felt that implementation would not be planned
until recommendations were made and there would have to be low
expectations for coverage during the first few years. Local solutions to
implementation would vary. The medical home does not have the capacity
to deliver influenza vaccinations to all school-aged children at this
point. Immunization programs and providers must maintain focus on
children at higher risk for influenza complications. School systems
might be interested, but they currently lack the means.]{.mark}

[Dr. Fiore touched briefly on some of the economic issues, based on
cost-effectiveness ratio estimates for the use of TIV and LAIV in
school-aged children. The current strategy is to use TIV in high-risk
children and the cost-effectiveness ratio measured here is dollars per
QALY, or quality-adjusted life-year. For the young children who
currently have a recommendation for vaccination, the ratios are fairly
low. As age increases, a routine vaccination recommendation would result
in cost-effectiveness ratios of over \$70,000 for the 5- to 11-year-olds
and over \$100,000 for the 12- to 17-year-olds.]{.mark}

[Vaccinating school-aged children also has indirect effects. The current
rationale for influenza vaccination recommendations in this country is
to reduce influenza and influenza complications in groups with the
highest rates of severe outcomes, including hospitalizations and medical
or emergency room visits and mortality, and also to provide vaccination
for anyone who wants to be vaccinated. Vaccinating children to reduce
transmission to contacts in the community would be a paradigm shift.
There is a growing literature on reductions in illness among contacts of
school-aged vaccinees in community demonstration projects. Coverage
among children in these projects has typically not exceeded 50 percent.
The most common model has been large-scale, school-based vaccination
programs, primarily using LAIV. There has been evidence of reductions in
school or work absenteeism, but reductions in severe outcomes among
contacts have not been demonstrated, perhaps because of small sample
sizes.]{.mark}

[Arnold Monto, a researcher in Michigan, provided a summary of the
evidence for indirect effects. Few studies are designed specifically to
examine issues of indirect protection, and those have used a variety of
designs, so it is difficult to use the standards applied to randomized
controlled trials to interpret these results. The evidence suggests
indirect protection, but it is difficult to quantify.]{.mark}

[David Shay discussed some of the challenges to measuring direct and
indirect effects after a school-aged vaccination recommendation.
Historical comparisons are problematic because of season-to-season
variability in influenza activity and vaccine effectiveness, patterns of
circulation of specific viruses, and the timing, duration and intensity
of activity for any given season. Existing community-level studies in
the U.S. could be expanded and adapted to evaluate the direct impact on
influenza illness in school-aged children. There is currently no easy
way to estimate the community-level indirect effects; this will require
multi-year studies, which are beyond current capacity. Assessments of
indirect effects should include lab-confirmed outcomes, if possible, in
at least a subset and data from more than one influenza season.]{.mark}

[Several consultants noted that recommendations to vaccinate school-aged
children could be justified simply by the direct benefits, even if
indirect effects are unknown. Indirect effects on the contacts and
community should be expected, but they might be difficult to prove.
Economists noted that vaccination of school-aged children has
cost-effectiveness ratios at the higher end of the range for currently
recommended vaccines (in the range of \$100,000 per QALY). However,
current economic studies are not taking all the indirect effects into
account because of difficulty getting consistent data on reductions of
influenza-related illness among contacts of vaccinees.]{.mark}

[Consultants noted that planning studies to measure impact must
accompany implementation. In Ontario, Canada, which currently has a
universal recommendation, it has been hard to show impact because it was
difficult to set up assessment tools at the same time the immunization
program was starting up. One suggestion was that extending the interval
between the recommendations vote and implementation would helpful for
planning for assessments and engaging providers and the public.]{.mark}

[In summary, school-aged children have the highest influenza attack
rates and are a major source of community transmission. They respond
well to the vaccine and have few adverse events. As many as 50% are
already recommended for vaccination. However, school-aged children are
at low risk for severe influenza complications and the cost to vaccinate
per QALY saved is higher than it is for young children or for children
at higher risk for influenza complications. Vaccinating school-aged
children with full implementation and good coverage will be difficult to
accomplish in traditional medical settings, and would require other
settings. This recommendation should reduce influenza illness among
contacts, but will be difficult to measure. There could be an impact on
rates of influenza in the community, but these will be difficult to
assess and will require multiple years of observation and careful
planning of assessments.]{.mark}

[]{.mark}

[**Summary of ACIP Influenza Working Group Discussions**]{.mark}

[]{.mark}

[Dr. Neuzil said there was strong consensus within the group on the
overall goal, but differences about strategies to reach that goal, which
is to try to control and prevent influenza and reduce the illness and
the complications from this disease. There is strong support for moving
towards universal influenza vaccination, but the best strategy is still
under discussion, particularly the timing of recommendation. A
recommendation could drive implementation, but it could also be damaging
to make a recommendation that is logistically not feasible. No one in
the group felt there were critical data gaps. There was also no clear
indication that more data would be available in the near term on
feasibility or indirect-protection issues.]{.mark}

[At the consultation meeting in September, practitioners said they were
dealing with an unprecedented number of new vaccine recommendations:
expansion of influenza, HPV, acellular pertussis, mening, and
second-dose varicella. So while the working group is committed to
gradually expanding the flu recommendations, practitioners and the
public just see a changing strategy every year. Waiting to expand the
recommendation allows time for more education and harmonization with
other organizations.]{.mark}

[The work group focused considerably on logistics. Vaccine supply was
not an immediate concern. If the expanded recommendation is to go into
effect next year, the time to vote would be now because providers and
clinics have to order vaccine before February. Manufacturers need to
know what to expect, but providers have a hard time knowing in December
and January what they are will need the following fall.]{.mark}

[A number of options have been discussed. Recommendations could be
expanded incrementally to an age-limited group: 5 to 11 years. However,
the group cautioned that there needed to be a consistent message about
what the ultimate recommendation would be. There is already a
recommendation to vaccinate anyone who wants to be vaccinated, so the
"consider" option was taken off the table. The question that remains is
how to make a recommendation that will drive people to prepare for
implementation but still allow a more time to do that.]{.mark}

[ ]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Morita asked whether there were any systems beginning to respond to
an eventual expanded recommendation. In Chicago some clinics are already
beginning mass immunization, which sets the stage for broadening to 5-
to 18-year-olds, but they will need more time. Public health is looking
into working with mass immunizers in the school setting for some of
adolescent vaccines.]{.mark}

[Dr. Craig favored recommending it now and letting groups work together
to catch up and implement it. Regarding school-based immunization
program, he did not think schools could be counted on to provide
vaccinations because of the huge amount of effort involved. Other ways
such as the medical home, public health clinics, and other mass clinics
would have to be used.]{.mark}

[Dr. Baker wondered whether, if one could demonstrate a decrease in
school days lost, that money could eventually support school-based
immunizations and capture the adolescents and school-aged children.
However, she felt the real issue was better immunization of 6- to
23-month-old children, who are at risk of hospitalization. The priority
should be doing a better job of immunizing those children for whom there
are good data, not a paradigm shift with a hope for indirect
effects.]{.mark}

[Dr. Lieu wanted to strongly consider making a recommendation now for
implementation downstream, because current systems are still struggling
to finish implementing the recommendation for the 6- to 23-month-olds
and the two- to five-year-olds. While providers could be educated in the
interim, it is difficult to educate people unless there is certainty
that it will happen.]{.mark}

[Dr. Judson commented that recommendations based on school-based
implementation are very difficult. It takes a huge amount of effort to
connect up the data systems so that the results get back to the medical
home and state reporting systems. These efforts compete with No Child
Left Behind and the increasing academic demands on the schools. Many
school districts will not appreciate a recommendation that does not help
with infrastructure and other support.]{.mark}

[Dr. Lett added that there would not be enough publicly purchased
vaccine to offer to all schoolchildren and most schools are not prepared
for billing. Community vaccinators with billing systems could be a
venue, either independent from school systems or perhaps in concert with
them, but this is a large undertaking.]{.mark}

[Dr. Cieslak believed that the process would never get started without
an ACIP recommendation. He wondered if vaccinating schoolchildren would
be just one more avenue for protecting the unvaccinated, vulnerable
children. Dr. Baker said she was a believer in the indirect effects, but
the committee had no data upon which to make a recommendation.]{.mark}

[Dr. Chilton appreciated the fact that the consultants and the working
group had considered logistics so heavily since the challenge of getting
the immunizations to children will be major. However, it provides an
opportunity to immunize those children who have medical indications and
have not been getting vaccinated. He added that implementation will be
largely local, not national.]{.mark}

[Ms. Stinchfield supported the recommendation going forward as soon as
possible, acknowledging the logistics are daunting. She applauded the
manufacturers who had made the great amount of doses available, but felt
distribution was still inadequate.]{.mark}

[Dr. Morse asked whether it was true that the economic estimates were
made in 2002 before the publicity around deaths in children and if so,
how much of an effect that could have. Dr. Fiore confirmed that the
survey the models were based on was conducted before the 2003-4
season.]{.mark}

[Mr. Beck commented that until the current plan is working properly, one
cannot sign people on to a new expanded plan. The keys seem to be
distribution and actual vaccination, which are not in keeping with the
current amount of vaccine available and the target audience.]{.mark}

[Dr. Schuchat appreciated the discussion about preparation and education
for the programs, the providers and the public. It would be helpful for
them to understand the purpose of the recommendation and the evidence
upon which it is based. Dr. Neuzil agreed that there was a
responsibility to report on whether goals had been met and that
recommendations should be made based on the direct effects, for which
there is strong evidence. If there are indirect effects, they would be a
bonus.]{.mark}

[Dr. Morita felt a recommendation could go forward with a delay in
implementation, because it would help people move forward with
implementing some of their current strategies. There would be value in
holding off on full implementation because the systems are not yet in
place.]{.mark}

[Dr. Poland thought there were two related but separate conversations.
One was about yet another incremental increase in school-aged
immunizations. The other was universal immunization. Two years ago the
ACIP signaled its intent to move toward a universal recommendation.
There are now 16 recommendations, which is confusing for practitioners
and paradoxically results in decreased immunization rates. Last year,
some 12 million doses of influenza vaccine were wasted, yet
manufacturers are asked every year to prepare for an increased number.
The question is whether the waste will increase or whether manufacturers
will scale back, creating a never ending Catch-22 cycle. There are
concerns that supply will be too low to meet demand, but neither history
nor the data show that to be the case. In every group for which the
vaccine is currently recommended, except for those over the age of 65,
immunization rates are 20 to 40 percent of those recommended to get the
vaccine. The target date for a universal vaccination was 2013, but that
was not based on science and logistics. He urged the ACIP to simplify
the recommendation to something like, "Influenza vaccination is
recommended for all eligible persons to reduce the risk of infection,
subsequent complications, and transmission to others," and then point
out that there are high-risk groups for whom vaccine is particularly
important. Implementation four and five years from now would have the
effect of paralyzing the system, so he urged the committee to say that a
universal recommendation would be in place in a year or two.]{.mark}

[Dr. Schmader said the American Geriatrics Society supports the expanded
use of flu vaccine in children as well as universal vaccination, because
it may reduce the burden of influenza illness in older adults,
recognizing that indirect-effect science is a bit inexact.]{.mark}

[Dr. Tan, American Medical Association, noted that influenza is an
annual vaccination and it is hard to achieve the same high coverage
rates as for DTaP or a traditional pediatric immunization. It will take
time to get resources in place at the local level and the ACIP
recommendation is critical for moving that process forward.]{.mark}

[Dr. Salisbury noted that the U.K. runs immunization campaigns in
schools on a one-cohort-per-year basis. These are incredibly
labor-intensive activities; doing it annually is an enormous burden and
hugely disruptive for schools. However it can be the best way to get
high coverage. The vaccine is free, so there is no issue about who
should have it or be charged. There is a great opportunity cost and
local providers expect to see compelling evidence that they should
redirect resources for these interventions. For primary-care providers,
it is another 50 percent over the usual number of people being
vaccinated over a six-week period for seasonal flu.]{.mark}

[Dr. Grogg, American Osteopathic Association, encouraged the ACIP to
move forward with a recommendation for universal vaccination,
understanding all the logistics and the difficulties of administering
vaccine to a large number of individuals.]{.mark}

[Dr. Temte offered three doctrines. First, the doctrine of fair warning.
Clinicians need a fair warning that this is coming. Second, simplicity.
Dealing with a universal recommendation is much simpler than remembering
16 separate risk-category groups. The third component is implementation.
It will be impossible to immunize everyone who should be, so just try
and get as many as possible. There is probably epidemiologic evidence
that getting more people immunized, regardless of who they are, has some
effect on transmission.]{.mark}

[Dr. Katz was concerned that it has not been possible to get even 35
percent of healthcare workers immunized. Education must come strongly
with any recommendation.]{.mark}

[Dr. Duchin wanted to see a national strategy that could be applied at
the local level by local health agencies, in conjunction with a
recommendation for a broad increase in the number of people who need to
be immunized. Local health officials' support of universal immunization
is based on the assumption of secondary indirect benefits and herd
immunity, so there needs to be a very clear rationale focused on direct
benefits to those immunized.]{.mark}

[Dr. Gellin reminded the group that this conversation had previously
been about supply and public confidence. Now it is about implementation
and better measurements are needed for implementation readiness. There
are plenty of outside-the-box solutions that can be considered.]{.mark}

[Dr. Foster, American Pharmacists Association, cautioned that there were
two groups driving this activity -- the providers and the patients, and
there has been little discussion of patients. Parents are the ones who
will go out of their way to get vaccines for their children.]{.mark}

[Dr. Tan wondered what would happen during a pandemic, if there is so
much concern about implementation and logistics now.]{.mark}

[Dr. Abramson felt it was clear that logistics was the key issue. He
thought there was sufficient capacity in the medical home if vaccination
clinics were set up early, before flu season.]{.mark}

[Mr. Hosbach of sanofi pasteur pointed out that when the ACIP makes a
recommendation, infrastructure, money, and action follow. Manufacturers
have now produced more supply than there is demand and there will be
even more next year. Whether it is universal recommendations or just the
existing recommendations, they need to be better implemented Second,
providers are still not paid adequately to immunize. Looking just at the
VFC program, at least half the states are reimbursing physicians for
administration fees of \$5 or less, and CMS is involved there. This
committee can have some influence there as well. Relative to
implementation, many people are still assuming100 percent uptake. Based
on claims data, from September 1, 2006, through January 31, 2007, an
estimated 42 million out of 58 million children ages 5 to 18, or 72%,
visited physician offices. The supply is here, but it may not stay in
the U.S.]{.mark}

[Dr. Mahadevia said that MedImmune conducted an economic analysis of
vaccinating school-aged children at school, in conjunction with the
University of Maryland. It was a large, cluster-controlled trial that
captured healthcare resource use and documented indirect effects to the
family and family members. After incorporating all of these factors, it
was found that vaccinating children at school may be cost-effective and
even cost-saving. Several factors need to be examined that influence the
economics, including mass efficiency, indirect costs associated with
transmission within the home, logistical resource use, and PR
campaigns.]{.mark}

[Dr. Eisenberg, Texas Medical Association, said the recommendation has
to be universal to get rid of the professional confusion. This is not a
burden, it is an opportunity to change the methodology and delivery of
healthcare in America, to allow medical homes to meet yearly with people
and emphasize the importance of preventive measures. Regarding
healthcare disparities, if the ACIP keeps making categories, the
underserved and underprivileged will not get vaccinated.]{.mark}

[Mr. Glen Moise, on behalf of Families Fighting Flu, implored that
committee to move forward on the recommendation and not let logistics
get in the way. It takes years for these recommendations to truly ramp
up and to have effect.]{.mark}

[Dr. Wexler, Immunization Action Coalition, pointed out that 74 percent
of the population is already recommended to get influenza vaccine, so it
seems like a no-brainer to move toward universal recommendation. This is
a completely different vaccine. It\'s given every year. There\'s no
catch-up period. We\'ll never get to 90 percent. We just have to do the
best we can and learn by doing. There is currently a recommendation to
vaccinate anybody who wants it, but reimbursement does not follow
without a recommendation. More than 250 organizations support a
universal recommendation for all school age children up through 18 years
of age, and they want to move forward.]{.mark}

[Dr. Baker, President of the National Foundation for Infectious
Diseases, or NFID, reminded members that a little over 20 percent of
children 6 to 59 months of age are getting their required two doses of
influenza vaccine. NFID has organized a childhood influenza immunization
coalition, which represents more than 25 professional, parent, and
public health organizations. Given the low immunization rate in this
highly vulnerable group, the coalition\'s mission is to make influenza
immunization in infants, children, and adolescents a national health
priority. The Web site is PreventChildhoodInfluenza.org.]{.mark}

[]{.mark}

**[Draft Guidance on Pandemic Vaccine Prioritization]{.mark}**

[]{.mark}

[Dr. Schwartz explained that in a pandemic, the goal would be to
vaccinate everyone, but with current technology, it will take at least
20 weeks until the first pandemic vaccine doses become available. Even
then, the U.S. vaccine-production capacity currently is not sufficient
to make vaccine rapidly for the entire population. Therefore, targeting
groups for earlier or later vaccination will best support national goals
of reducing the health, societal, and economic impacts of the next
pandemic. HHS has invested over \$1 billion to increase vaccine
production capacity, develop and license new vaccine-production
technologies, and evaluate adjuvanted vaccine formulations.]{.mark}

[Mathematical modelers hypothesizing a first pandemic outbreak in
Southeast Asia predict almost two months until the first U.S. case and
another 80 to 120 days from the first case to the peak of the first
pandemic wave, but there is substantial uncertainty with a wide range
around these point estimates. It is unknown where a pandemic would begin
and during which season. In 1957, the pandemic virus was first
introduced into the United States in early June. Not a single community
outbreak occurred until mid August, and the peak of the first pandemic
wave did not occur until the end of October.]{.mark}

[Vaccine supply depends both on U.S. based capacity at the time of the
pandemic and the antigen concentration needed in each dose for good
immunogenicity. For example, with candidate H5N1 vaccines, the antigen
concentration in clinical trials has ranged from 3.8 to 90 micrograms,
depending on the vaccine formulation, suggesting a 24-fold range in the
number of doses that may be available. These uncertainties highlight the
importance of a prioritization strategy.]{.mark}

[The first effort at vaccine prioritization occurred in 2005 as a joint
activity of ACIP and NVAC. This process considered vaccine supply and
efficacy; the impacts of past pandemics among different age and risk
groups; the potential impact on critical infrastructures, particularly
on healthcare; and ethics. The priority groups were identified in four
tiers with several sub-tiers. The highest priority groups included
healthcare providers, high-risk individuals, and the elderly, which
reflects current vaccine recommendations. Only after 100 million people
had been targeted for vaccination would critical infrastructure sectors
outside of healthcare and some public health responders would be
targeted.]{.mark}

[Several factors led to reconsideration of this prioritization strategy.
Planning assumptions evolved from a moderate pandemic to one that was
more severe, extrapolated from the 1918 pandemic, having a higher
case-fatality rate and substantial absenteeism, assumed on the basis of
illness as well as fear of reporting to work. In four public engagement
meetings, participants indicated that it was critical to protect
essential services before protecting high-risk individuals. Finally, an
analysis by the National Infrastructure Advisory Council defined the
critical roles and the interdependencies among critical infrastructure
sectors and identified specific priority groups for vaccination.]{.mark}

[An interagency working group was created, co-led by HHS and the
Department of Homeland Security with representatives from across the
federal government, recognizing that a severe pandemic would be a
national emergency affecting all sectors and security and critical
infrastructure issues would be a major focus. Interagency involvement in
drafting the guidance helps educate those sectors and facilitates policy
approval.]{.mark}

[The working group considered prior ACIP and NVAC recommendations;
scientific, public health, and ethical issues; analysis and
recommendations on critical infrastructure by the National
Infrastructure Advisory Council; and national and homeland security
issues. Two public engagement meetings and a stakeholders meeting were
held, a formal decision analysis was conducted, and comments were
received in response to a Federal Register and PandemicFlu.gov notice.
Other participants included representatives from CDC, ASTHO and NACCHO.
There were presentations from the Department of Defense, the U.S. Secret
Service, and mathematical modelers.]{.mark}

[The working group heard from ethicists at NIH and the Minnesota Center
for Health Care Ethics, who had considered vaccine prioritization issues
previously. Ethical discussions included the importance of transparency
and inclusiveness as well as reasonableness, which means listening to
the values and priorities of the community and the public when there is
no single scientific best answer. Preserving society was considered of
greater importance than protecting individuals in a severe pandemic.
Other key issues were fairness, valuing all life equally and treating
everyone in a priority group the same way; reciprocity, defined as
protecting those who assume occupational risks in order to benefit
society; and flexibility, reconsidering the strategy periodically and
again at the time of the pandemic.]{.mark}

[An analysis was done of the essential functions of critical
infrastructure and key resource sectors, their interdependencies, and
the specific work forces needed to maintain essential functions. This
would include the utilities, healthcare, and emergency services, as well
as such sectors as banking and finance, chemical, food and agriculture,
transportation, oil and natural gas. Results suggested that of the 85
million workers in these sectors, about 12.4 million, almost 15 percent,
would be critical for maintenance of essential functions. Almost half
are in healthcare; the next largest number is in the emergency service
sectors, which include EMS, law enforcement, and fire
protection.]{.mark}

[Public engagement and stakeholder meetings were held to consider the
potential goals of pandemic vaccination. After background presentations
and discussion, participants indicated how they valued each of ten
potential objectives. The public engagement meeting held in Las Cruces,
New Mexico had 108 persons, many of whom were Hispanic, ranging from
college students to older adults. In Nassau County, New York, about 130
persons participated, and many were older adults. The stakeholders\'
meeting in Washington, D.C., had over 90 representatives from
government, critical infrastructure sectors, and community
organizations.]{.mark}

[The top four objectives for pandemic vaccination were the same at all
three meetings: protecting people working to fight the pandemic and to
provide care; protecting those who provide essential community services;
protecting people who are most vulnerable due to their jobs; and
protecting children. Over a quarter of those who attended the public
meetings were over age 65. Even though it was made clear that older
persons are at greater risk of severe disease and mortality, children
were given higher priority. More than one stated that they would prefer
that the vaccine be given to their grandchildren rather than
themselves.]{.mark}

[A decision analysis was conducted in collaboration with the University
of California, Berkeley, and the California Department of Health.
Fifty-seven different population groups were defined by their job, age,
and health status, and rated by the extent to which each met the
occupationally related objectives, such as providing essential services,
being at risk due to their jobs, or protecting homeland or national
security. CDC and external influenza experts then rated the extent to
which each group met the science-based objectives of vaccine
effectiveness, the risk of severe illness and death, and the likelihood
of transmitting infection. Weights based on the public and stakeholder
values were applied to obtain a single score for each population group.
The highest ranked groups included public health responders, healthcare
workers, EMS providers, law enforcement, and children, which was
consistent with the public and stakeholder values and ethical
principles.]{.mark}

[The draft guidance recommends that vaccination be administered in
tiers, each including several target groups defined according to the
objectives of protecting healthcare and community support services,
critical infrastructure, homeland and national security, and protecting
the general population. Target groups are then clustered into levels,
within which each of the groups has a similar priority for vaccination;
each vaccination tier combines target groups across categories. In
addition, there are three sets of recommendations, depending on the
severity of the pandemic.]{.mark}

[The top tier for vaccination is the same regardless of pandemic
severity. For critical infrastructure, it includes emergency services,
EMS, police, and fire, because these individuals will have an increased
burden in a pandemic, a high risk of exposure, and little surge
capacity. The second tier for critical infrastructure includes the
utilities because every other sector of society depends on the
maintenance of these services. The third group includes food and
agriculture, banking and finance, other critical infrastructure sectors.
The general population recommendations begin with pregnant women,
infants, and toddlers, followed by household contacts of infants too
young to be vaccinated, other children, and then high-risk adults and
the elderly. In a severe pandemic, the final tier is healthy adults 19
to 64 years old.]{.mark}

[Activities during the two-month comment period include a request for
comments in the Federal Register and on the HHS Web site, presentations
to ACIP and NVAC, public engagement and stakeholder meetings, as well as
a Web-based public-engagement process. The group will work with
infrastructure sectors to validate the population estimates and with
infrastructure and public health officials to consider options for
implementation. The final interim guidance will reflect the evolution of
science and technology, but as more is learned, the guidance may
change.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Morse noted that comments from ACIP should be coordinated with
NVAC. Dr. Schwartz replied that formal comments should be submitted
before the next ACIP meeting in February.]{.mark}

[Dr. Baker pointed out that pregnant women and children 6 to 23 months
were a top priority in all scenarios and encouraged NIH to also consider
those populations as priorities for their avian flu and influenza
studies.]{.mark}

[Dr. Neuzil commented that CDC and HHS and other partners were looking
at antivirals and business and personal stockpiles, and that those
efforts should be coordinated so that the same people who get the
antivirals are not also getting vaccine. She added that ACIP had a
clearly defined mandate relating to vaccine recommendations, but
wondered how that would change during a pandemic. Dr. Schwarz responded
that there was coordination of strategies, including for other response
measures such as the use of personal protective equipment, respiratory
protection, masks and respirators, as well as community mitigation and
social distancing, and other strategies that will provide protection in
business sectors and elsewhere before vaccine becomes available. During
a pandemic, CDC will be collecting epidemiological information which it
could present to the ACIP because of its experience in making vaccine
recommendations, but this would clearly be a policy decision.]{.mark}

[Dr. Plotkin pointed out that the lowest priority group was the 19- to
64-year-old age group, which is the most productive age group. He
suggested that more priority be given to those who are contributing to
society rather than the elderly.]{.mark}

[]{.mark}

**[Cost-Effectiveness of Influenza Vaccination: Updated Estimates for
Children Aged 2-4 Years]{.mark}**

[]{.mark}

[Dr. Prosser presented data from a study funded by the CDC-Harvard Joint
Initiative in Vaccine Economics, carried out to update a previously
published cost-effectiveness analysis of influenza vaccination in
children, incorporating current cost estimates and adding wheezing
episodes and hospitalization as possible adverse events following
vaccination. The specific strategies in this analysis were vaccination
with either inactivated vaccine or live attenuated vaccine compared with
no vaccination.]{.mark}

[A computer simulation was developed to estimate cost and effects for
children aged two to four years. Children were divided into two age
groups and stratified by their risk for influenza-related complications,
resulting in four subgroups. Endpoints in the model were otitis media
and non-hospitalized pneumonia. Cost and quality adjustments associated
with each health state are included in the model, as well as
vaccination-related adverse events.]{.mark}

[The primary endpoint for the analysis was the incremental
cost-effectiveness ratio, calculated by dividing the difference in cost
under vaccination or no vaccination by the difference in events for
vaccination and no vaccination. Net costs and net events averted for the
different endpoints in the model weere also reported. A number of
sensitivity analyses were conducted, including one-way sensitivity
analyses on all parameters and a probabilistic sensitivity analysis in
which all parameters were varied simultaneously.]{.mark}

[Inputs were derived from both primary and secondary data sources and
fell into four main categories: the natural history of influenza in
children, effects of vaccination, costs, and adjustments for quality of
life. A societal perspective was used for the analysis, and the time
frame was one year, except that costs and quality adjustments for
long-term outcomes such as death and long-term sequelae were
included.]{.mark}

[Each of the parameters in the model was represented by a distribution,
not a point estimate. So for the probability of influenza, the base-case
value for two-year-olds that are not at high risk for influenza-related
complications was 0.155. The 95 percent confidence interval or the range
over which this probability was varied, was .02 to .35. Probabilities
varied by age and by risk group within the model.]{.mark}

[One of the key endpoints in the model was the quality-adjusted
life-year, or QALY. A QALY can be roughly described as being equivalent
to a year in perfect health. Most of the health states in this
simulation were temporary and modeled as the loss in quality-adjusted
life-years due to a particular event. To derive estimates for the QALY
losses, parents were asked about the amount of time they would be
willing to trade off from their own lives to avoid an influenza illness
in their child. For uncomplicated influenza illness, the mean amount of
time parents were willing to trade from the end of their life was 68
days. To calculate the QALY loss, the discounted time traded was divided
by the discounted life expectancy, in this case, a mean quality-adjusted
life-years lost of .005 for an uncomplicated episode of
influenza.]{.mark}

[A follow-up study is currently being conducted in a national sample of
respondents, which will include hospitalization related to influenza. In
the upcoming survey, four different age categories for children will be
included \-- 1, 5, 8, and 15 years \-- and also four different age
categories for adults. The pilot results from a sample size of 200 look
very similar to uncomplicated influenza.]{.mark}

[The previous analysis included systemic reaction, anaphylaxis, and
Guillain-Barre Syndrome as possible adverse events to vaccination. For a
live attenuated vaccine, wheezing episodes and hospitalization following
vaccination have been added.]{.mark}

[Vaccine-dose costs for inactivated vaccine included thimerosal-free
vaccine for children under three and reflect 2006 purchase prices. The
other costs have also been updated to 2006 dollars. For live attenuated
vaccine, the costs of treating an episode of wheezing and for
hospitalization following a wheezing event have been added. Total
vaccination costs include cost of the vaccine dose, administration
costs, and parent-time costs. It was estimated that it could take up to
two additional visits for a previously unvaccinated child to receive
both doses, but that others would require none or only one additional
visit. Parent-time costs make up a substantial portion of total
vaccination costs. QALY adjustments have also been updated to include
QALY losses for wheezing episodes and hospitalization following
vaccination. The QALY loss for wheezing is equivalent to about one day
of a quality-adjusted life-year lost due to a wheezing episode.]{.mark}

[Results in terms of net costs and episodes averted were similar for
inactivated and live attenuated influenza vaccine. Net costs were
slightly higher for live attenuated vaccine, and averted events were
also slightly higher. However, confidence intervals around these
estimates were wide. Projecting these estimates for the U.S. population
would result in additional costs of approximately \$54 million if all
eligible children aged two to four received live attenuated vaccine
instead of inactivated vaccine, with an additional savings of about
250,000 influenza events averted. This assumes, however, 100 percent
vaccination coverage in these groups and would be lower at the current
rate.]{.mark}

[Cost-effectiveness ratios were also similar for inactivated and live
attenuated vaccine. Using QALYs as a measure of health benefit allows
one to combine all the benefits from the averted episodes included in
the other ratios into one number. The cost-effectiveness ratio in
dollars per QALY gained is \$25,000 for inactivated vaccine and \$23,000
per QALY for live attenuated vaccine among 2-4 year olds, similar to
results from the previous analysis. For all of the age-risk groups
considered in this updated analysis, ratios were most cost-effective in
the high-risk subgroups and increased with increasing age, consistent
with previous analyses.]{.mark}

[The probability of influenza illness had the greatest effect on
cost-effectiveness ratios. For years in which there is little influenza
illness, cost-effectiveness ratios are substantially higher.
Cost-effectiveness ratios were not sensitive to the probability of
wheezing or hospitalization following vaccination over the range
included in the base-case analysis, so a wider sensitivity analysis was
conducted to look at a very large range of probabilities of
hospitalization following vaccination. The base-case rate is less than
.001, and as the probability of hospitalization increases beyond .006,
inactivated vaccine becomes the preferred strategy, because it becomes
less costly and provides greater health benefits.]{.mark}

[To summarize, results were similar to previously published
cost-effectiveness analysis in that live attenuated vaccine had similar
or better cost-effectiveness ratios than inactivated vaccine for
eligible age-risk groups. The inclusion of possible new adverse events
had varying effects. Results were not sensitive to an outpatient
wheezing episode, but were sensitive to a possible increase in all-cause
hospitalization.]{.mark}

[There are several limitations to this analysis. Effects of herd
immunity were not considered and would likely make the
cost-effectiveness ratios more favorable. Data are limited on some key
assumptions, such as the probability of an outpatient visit for
influenza, and results were somewhat sensitive to this parameter.
Importantly, quality adjustments used for adverse events may not fully
reflect the negative value some parents may ascribe to these risks, and
it is hard to fully capture this in the cost-effectiveness
framework.]{.mark}

[When looking at updated cost-effectiveness ratios for all age and risk
groups, cost-effectiveness varies primarily by risk status and increases
with increasing age. Vaccination for non-high-risk two- to
four-year-olds, therefore, yields ratios that are higher than high-risk
children of all ages, but lower than those for school-aged
children.]{.mark}

[In the context of recently recommended vaccines by ACIP,
cost-effectiveness ratios range from cost-saving to more than \$100,000
per QALY gained, and influenza vaccination of non-high-risk two- to
four-year-olds with LAIV falls within this range.]{.mark}

[In summary, the inclusion of new adverse events has little impact on
the cost-effectiveness of live attenuated vaccine, except if the
probability of all-cause hospitalization is higher than reported in the
trials. Consistent with previous results, LAIV was more costly but also
more effective, yielding slightly better cost-effectiveness ratios than
inactivated vaccines.]{.mark}

[]{.mark}

[]{.mark}

**[Pediatric Use of Pneumococcal Vaccines]{.mark}**

**[Dr. Julie Morita, ACIP, WG Chair]{.mark}**

**[Dr. Pekka Nuorti, CDC/NCIRD/DBD]{.mark}**

[]{.mark}

[Dr. Morita explained that the working group had reviewed the use of the
pneumococcal polysaccharide vaccine in persons aged 50 to 64, the
preventability of invasive disease based on current or expanded
recommendations, and optimal timing and frequency of revaccination with
the pneumococcal polysaccharide vaccine. For the pediatric population,
the working group reviewed pneumococcal immunization in HIV-infected
school-aged children and the use of the pneumococcal conjugate vaccine
in incompletely vaccinated children 24 to 59 months of age. Some
overlapping topics included the use of the pneumococcal vaccines during
an influenza pandemic, whether or not hypo-responsiveness is an issue
with multiple doses of the pneumococcal polysaccharide vaccine, and
asthma without high dose corticosteriod use as a potential indication
for pneumococcal vaccination.]{.mark}

[In the coming months, the group will finalize recommendations for the
use of the polysaccharide vaccine in high-risk children aged two and
older who have already received the conjugate vaccine and review
potential time lines for the new pneumococcal vaccines. Recommendations
for changes with the conjugate and the polysaccharide vaccine will be
presented in February or June.]{.mark}

[]{.mark}

**[Use of Pneumococcal Conjugate Vaccine (PCV4) in 24-59-month-old
Children who are Incompletely Vaccinated]{.mark}**

[]{.mark}

[Dr. Nuorti reviewed the current ACIP language for use of PCV7 in older
children as stated in the *MMWR* 2000: *"PCV7 is recommended for
children aged 24 to 59 months who have certain underlying diseases or
immunocompromising conditions."* A list of these underlying medical
conditions is given and no revisions were to be proposed to that list
itself. The ACIP statement also indicates that PCV7 should be considered
for all other children aged 24 to 59 months, with priority given to
children who are Alaskan Native, American-Indian or African-American
descent and for children who attend group day-care centers. For children
who have underlying medical conditions, the recommendation is to give a
subsequent dose of the pneumococcal polysaccharide vaccine, administered
two or more months after the last dose of PCV7. No changes are currently
proposed for the polysaccharide vaccine recommendation.]{.mark}

[Some immunization providers have found the current permissive
recommendation confusing and frequently call the NIP Info Hotline for
clarification. In addition, historically, the routine catch-up
recommendation was limited to those with underlying medical conditions,
partly because of concerns about vaccine supply, cost issues, and lack
of data on vaccine effectiveness. The work group felt that simplifying
and expanding the catch-up recommendation may improve PCV7 coverage
among healthy unvaccinated or incompletely vaccinated children aged 24
to 59 months, including immigrants and adoptees from countries not using
PCV7.]{.mark}

[Data from the CDC Active Bacterial Core surveillance system on the
remaining disease burden of overall and PCV7-type invasive pneumococcal
disease show differences between two age groups. The rates of
vaccine-type disease in two- to four-year-olds are very low. In the last
couple of years, they have been in the order of 1 to 2 cases per 100,000
per year, compared to about 2 to 3 cases in the under-twos. Among 150
cases of invasive pneumococcal disease identified in 2006, only 9.3
percent had any of the underlying medical conditions that are a PCV
indication. Rates of PCV7-type invasive pneumococcal disease are very
low in this age group because of almost eight years of routine conjugate
vaccine immunization and indirect effects. However, the working group
feels there is a potential additional benefit from increased individual
protection and induction of immunologic memory, and possible prolonged
protection for those children who are incompletely vaccinated.]{.mark}

[PCV7 generally is safe and immunogenic in children aged 24 to 59
months, although local reactions are more common in older than younger
children. In the post-licensure population-based case-control study,
vaccine effectiveness was good even for one dose of PCV given at 24
months or older; the point estimate was 94 percent with a 95 percent
confidence interval from 49 to 99. In that same study, a four-dose
schedule, given as three primary doses and a booster, was significantly
more effective than just a primary three-dose schedule. In the 2006
National Immunization Survey, the four-dose vaccine coverage among 19-
to 35-month-olds was 68.4 percent and 87 percent received three or more
doses. Thus the expanded catch-up recommendation could apply to up to
one-third of the children in this age group.]{.mark}

[The working group\'s proposal for a revised recommendation for healthy
children reads, *"At ages 24 to 59 months, administer one dose of PCV7
to healthy children with any incomplete schedule."* The revised
recommendation for children with underlying medical conditions only
specifies the number of previously received doses, otherwise it is
similar to what was given in the *MMWR* 2000. *"At ages 24 to 59 months,
administer two doses of PCV7 at least two months apart to incompletely
vaccinated children with underlying medical conditions. Those who have
previously received three PCV7 doses need only one dose."*]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Baker asked what the reason was for saying two doses at least two
months apart for the children with underlying medical conditions
incompletely immunized. Dr. Whitney from Respiratory Diseases Branch
explained that it was based on immunogenicity study data.]{.mark}

[Dr. Pickering asked what the group's plans were for updating the 2000
*MMWR* pneumococcal publication. Dr. Nuorti replied that the plan was to
merge the 1997 and 2000 *MMWR*s that related to the polysaccharide
vaccine or the conjugate vaccine. Since the time line for the extended
valent pneumococcal conjugate vaccines was still unclear, the plan was
to revise that statement in 2008.]{.mark}

[Dr. Cieslak noted that the incidence of disease from the seven
serotypes was around 1 per 100,000 for healthy children 24-59 months and
wondered if there were any cost-effectiveness data on preventing a case
of illness in that population. Dr. Nuorti replied that no formal
cost-effectiveness analysis had been done on this expanded
recommendation. Dr. Judson added that one approach was to ask how much
disease a fourth or additional dose of vaccine would prevent on a
population basis and what it would cost. He suspected it might not be a
favorable ratio. Dr. Nuorti responded that the recommendation would
potentially apply to a rather large group of children, where the rates
of vaccine-type disease are very low. The working group is making this
recommendation because of the potential added benefit at the individual
level and the induction of immunologic memory that may result in
prolonged protection for unvaccinated or incompletely vaccinated
children. The current language states that PCV7 should be considered for
all children in this age group with priority given to the groups
mentioned. The proposal is to move from a confusing permissive
recommendation to a straightforward recommendation that would apply to
all children.]{.mark}

[Dr. Hull asked if the proposed recommendation was dropping the
supplementary dose of PCV23 for the high-risk children. Dr. Nuorti
clarified that the proposed recommendation about the subsequent
pneumococcal polysaccharide vaccine dose for children with underlying
medical conditions remained unchanged.]{.mark}

[Dr. Lieu said she had led the original analysis of pneumococcal
conjugate vaccine in 1999-2000, at which time the group looked at the
cost-effectiveness of catch-up vaccination. Catch-up programs never
appear to be as cost-effective as a basic recommendation. The proposed
recommendation does add some vaccination, but cost should not be a huge
barrier because it is one dose for children who actually are incomplete
at the time. Dr. Schuchat commented that catch-up campaigns often do not
seem cost- effective because the disease rates decrease. However, there
is the additional factor of a phenomenal herd effect. The two- to
four-year-old pre-vaccine era rates were lower than the under-two rates,
and now they are almost zero.]{.mark}

[Dr. Judson asked how many children who had received three doses and not
adequately responded would do so with a fourth dose. Dr. Nuorti replied
that some of the effectiveness data from the CDC case-control study
suggest that children who have received the primary three-dose series
plus a booster dose show better efficacy compared with those who have
only received three doses. For the conjugate vaccine booster, one of the
issues is the reduction of nasopharyngeal carriage and transmission that
leads to herd effects. Dr. Baker added that there is also the issue of
duration of protection, because a two-four-six is done and conjugate
vaccines need a booster. Dr. Paradiso commented that it matters when the
three doses are given. If they are given in the first year of life
without the booster dose, it is more of an issue. If the third dose is
given later in life, the booster is needed less. It is about carriage in
particular and long-term durability of protection.]{.mark}

[Dr. Chilton suggested that the cost per invasive disease prevented
would be about \$160,000, assuming 1 case per 10,000 and that the
vaccine costs \$50.]{.mark}

[Dr. Nuorti reviewed the proposed recommendation for healthy children:
*"At ages 24 to 59 months, administer one dose of PCV7 to healthy
children with any incomplete schedule. And for children with underlying
medical conditions, at ages 24 to 59 months, administer two doses of
PCV7 at least two months apart to incompletely vaccinated children with
underlying medical conditions. Those who have previously received three
PCV7 doses need only one dose."*]{.mark}

[Ms. Stinchfield suggested that the first sentence begin with the words,
"For healthy children," which would help providers.]{.mark}

[Dr. Campos-Outcalt asked whether "incompletely vaccinated" meant less
than four doses. Dr. Nuorti replied that it means zero to three doses.
Dr. Judson pointed out that zero doses would not be incompletely
immunized. Dr. Nuorti said the statement could say unimmunized or
incompletely immunized.]{.mark}

[Dr. Whitney clarified that there could be children who just received
two doses, for example, after one year of age, and they would be fully
vaccinated. Dr. Campos-Outcalt said that was his confusion, whether
children who start late but then receive the recommended number of doses
are considered incompletely vaccinated for this recommendation. Dr.
Nuorti replied that when the vaccine was introduced and the
recommendation initially made, there were many different schedules and
children may have received the polysaccharide vaccine dose before in
this category. Based on data from the National Immunization Survey, the
likelihood is that most of the incompletely vaccinated children have
received at least three doses, but this would also apply to those who
had received fewer than three doses. Dr. Lett asked if the
recommendation would still say "who are unimmunized or incompletely
vaccinated for age". Dr. Wallace responded that it was not only about
the number of doses, but when children get them. In the catch-up
schedule, all those caveats are covered by age.]{.mark}

[Dr. Bocchini asked whether this wording would now be consistent with
the Red Book and the AAP. The Red Book currently says that for 24- to
59-month-old children who are healthy with any incomplete schedule,
consider one dose at two or greater months after the most recent dose.
For children at high risk, for any incomplete schedule of less than
three doses, one dose greater than two months after the most recent dose
and another dose two months later. For any incomplete schedule of three
doses, give one dose greater than two months after the most recent dose.
Dr. Morse noted that this editorial clarification should be
made.]{.mark}

[Dr. Baker moved approval of the recommendation and Dr. Craig seconded
the motion.]{.mark}

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

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

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

[Dr. Cieslak; no.]{.mark}

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

[Dr. Chilton; no.]{.mark}

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

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

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

[Dr. Judson; no.]{.mark}

[Dr. Lieu ; yes.]{.mark}

[Dr. Craig; yes.]{.mark}

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

[Dr. Englund; yes.]{.mark}

[Dr. Morse: The motion carried.]{.mark}

**[Meningococcal Conjugate Vaccine (MCV4)]{.mark}**

**[Dr. Carol Baker, ACIP WG Chair]{.mark}**

**[Dr. Thomas Clark, CDC/NCIRD/DBD]{.mark}**

**[Dr. Greg Gilmet, sanofi pasteur]{.mark}**

**[Dr. Amanda Cohn, CDC/NCIRD/DBD]{.mark}**

**[Dr. Greg Wallace, CDC/NCIRD/ISD]{.mark}**

[]{.mark}

**[Introduction]{.mark}**

[]{.mark}

[Dr. Baker reviewed MCV4, or Menactra quadrivalent meningococcal
conjugate A/C/Y/W-135 vaccine, which was licensed in 2005 for use in
those 11 through 55 years of age. There was an ACIP recommendation for
use in these age groups, a routine recommendation for adolescents in
certain cohorts, and a recommendation that MCV4 would be preferred in
those at increased risk of disease. College freshmen who will be living
in dormitories and patients with functional anatomic asplenia are
considered at increased risk. The first cohort was routine use in 11- to
12-year-old adolescents. This was the first vaccine for the "adolescent
platform." The second cohort was at high-school entry or age 15, based
on the epidemiology suggesting an increased attack rate in this group.
Because of a number of factors, it was changed in June 2007 to all
adolescents not previously immunized with MCV4. The meningococcal
polysaccharide vaccine is currently recommended for children two to ten
years old at increased risk of disease.]{.mark}

[Since the recommendation was published, there have been three *MMWR*
publications on Guillain-Barré syndrome and MCV4, one *MMWR* on
inadvertent administration where vaccine was given subcutaneously rather
than intramuscularly, two notices to readers on supply, and one notice
to readers on the revised recommendation (all adolescents 11 through 18
years of age). On October 18, the FDA licensed MCV4 or Menactra in two-
to ten-year-olds.]{.mark}

[]{.mark}

**[Update: Meningococcal Vaccine Safety]{.mark}**

[]{.mark}

[Dr. Clark reminded the committee that Guillain-Barré syndrome (GBS) is
a subacute onset demyelinating neuropathy characterized by bilateral
flaccid paralysis. It is thought to have an autoimmune etiology. In
about 50 percent of cases, a precipitating cause can be identified. In
15 to 40 percent of those, the cause is usually Campylobacter with other
post-infectious etiologies in decreasing frequency. Some cases in the
past have been vaccine associated. No clear seasonality has been
observed in Western countries, but incidence increases with age and
there is a suggestion recently of a decreasing secular trend in the
United States. Relative to adults, children have an improved prognosis
with roughly half ambulatory at six months, 70 percent ambulatory at one
year, and 3 to 4 percent mortality.]{.mark}

[During the 1976/A/New Jersey/Swine Flu mass-vaccination campaign,
vaccine was provided for most of the U.S. adult population and at-risk
children, but the program was halted following a number of reports of
GBS following vaccination. Later studies confirmed an association
between this vaccine and GBS, with an attributable risk estimate in six
weeks following vaccination ranging from 4.9 to 11.7 cases per million
vaccine recipients. Subsequently, the Institute of Medicine reviewed
data and determined that the evidence favored a causal relationship. The
epi curve of the association shows a clustering in the two to three
weeks following vaccination and peaking at a relative risk of about
15.]{.mark}

[In the 1978-\'79, \'79-\'80, and \'80-\'81 seasons, there was no
observed association of influenza vaccination with GBS. During the
\'93-\'94 vaccination season, GBS case reports increased, and a
case-control study was conducted, looking at the \'92-\'93 and \'93-\'94
seasons. Individually, there was no statistically significant
association of GBS with vaccines, but for both seasons combined, there
was a relative risk of 1.7 and the 95 percent confidence interval just
crossed 1, which translates to about one excess case per million
vaccinees. The IOM subsequently concluded that the evidence in these
cases was inadequate to accept or reject a causal relationship. The ACIP
has chosen to manage this risk by saying that, while there may be an
association in some seasons, the measured magnitude of the risk is small
and the potential benefits of influenza vaccination in preventing
serious illness, hospitalization, and death substantially outweigh
estimates of risk for vaccine-associated GBS.]{.mark}

[In the U.K. all 1- to 20-year-olds were vaccinated with Serogroup C
meningococcal vaccines, with no substantially increased incidence of
Guillain-Barré syndrome. In ten years of reviewed experience with MPSV4
in the U.S., there was one case.]{.mark}

[As of October 2997, 24 vaccine-associated cases have been reported to
VAERS, reviewed and categorized according to Brighton criteria; 22 of
those were among 11- to 19-year-olds. From the VSD Rapid Cycle Analysis,
which includes over 213,000 doses of conjugate vaccine administered,
there were zero observed cases among 11- to 19-year-olds within six
weeks of receipt of vaccine; the expected number ranges from zero to
one. The Brighton GBS classification criteria use increasing evidence
for Guillain-Barré syndrome to classify cases in increasing levels of
certainty. The clinical case definition just includes the subacute
flaccid paralysis or cranially nerve innervated muscles effected. The
third or lowest level includes some other clinical characteristics. The
second level includes the illness pattern as well as
cyto]{.mark}-albuminologic [dissociation on CSF, and the most definitive
or Level 1criteria include EMG findings.]{.mark}

[When medical records of the 22 cases were reviewed, 32 percent met
Level 1 criteria; 64 percent, Level 2; and 4 percent, Level 3. Among the
22 cases, 45 percent were male, 55 percent had received conjugate
vaccine alone, and 86 percent were hospitalized. Among the 21 with
evidence in the charts, nine had been hospitalized in intensive care.
One patient was intubated, three were plasmapheresed, and 18 received
IVIG as treatment. Among the 19 that were hospitalized, 15 were
ambulatory at the time of discharge. eight had disability affecting
activities of daily living, and 5 were discharged to inpatient rehab
treatment. Looking at cases by month of onset, there was no significant
increase in reports after licensure in January 2005, but the October
2006 *MMWR* reported on 17 cases and since then there have been more
five cases.]{.mark}

[The epi curve of doses of vaccine distributed shows that in October
2006 there were 17 cases out of about 6.5 million doses. Since then,
distribution of doses has increased significantly, so that 22 cases in
11.5 million doses have been reported. Looking at timing of onset, there
is a statistically significant cluster between Days 9 and 16, with 13
cases in that interval. Currently, among 11- to 19-year-olds, 22
reported cases results in an incidence ratio of 1.3, with a confidence
limit that crosses 1. That is roughly 0.4 excess cases per million doses
of vaccine. Twenty of the cases are in 15- to 19-year-olds, where the
incidence rate ratio is 1.7 with a confidence interval just above 1.
That is 1.3 excess cases per million doses of vaccine.]{.mark}

[To do a sensitivity analysis, the study varied the incidence rate ratio
by cases underreported and by doses not administered. The 1.7 incidence
rate ratio assumes 100 percent reporting and 100 percent doses
administered. Varying either of those to 70 percent results in an
incidence rate ratio of 2.4, while varying either to 50 percent results
in an incidence rate ratio of 3.4. Dropping both to 50 percent results
in an incidence rate ratio of 6.7. The worst-case scenario would result
in 11 excess cases per million vaccinees.]{.mark}

[Next a probabilistic decision analysis was conducted, using a
cohort-simulation model that compared health outcomes in a full
meningococcal vaccination program to no meningococcal vaccination,
including an associated risk of Guillain-Barré syndrome. An
11-year-birth cohort of 4.1 million persons was modeled over an
eight-year period, using the patient perspective. Health outcomes
included cases of meningococcal disease and GBS; deaths; life-years
lost; and quality-adjusted life-years lost, or QALYs. Parameters and
assumptions included 5 percent long-term morbidity associated with GBS
among adolescents and a GBS incidence in unvaccinated persons of 1.4 per
100,000. These were taken from Vaccine Safety Datalink and Healthcare
Utilization Project, and an incidence of GBS in vaccinated persons
estimated by VAERS reports, which was roughly 1.8 per 100,000 at the
time. For meningococcal disease, vaccine efficacy was estimated at 93
percent, based on the U.K.experience and a disease rate in unvaccinated
persons of 0.77 per 100,000. A disease incidence in unvaccinated persons
of 0.05 was used, calculated using the vaccine efficacy. An age-specific
case fatality ratio was applied per year of life, averaging out to 10.34
percent.]{.mark}

[In a probabilistic model, the range of values for the parameters
varies, each with an associated probability. The lower bound of the GBS
incidence in this case in vaccinated persons was 1.4 and the upper bound
was three times 4.2 cases per 100,000, which results in five excess
cases of GBS over the cohort or an attributable risk of roughly 1.25 per
million. Full vaccination compared to no vaccination prevented 359 cases
of meningococcal disease and 35 deaths, and overall, full vaccination
prevented 2,254 QALYs lost.]{.mark}

[In a sensitivity analysis on the decision analysis, the variability of
GBS incidence in vaccinated persons was increased to include a relative
risk of 6.7. The 6.7 was taken as the 75th percentile, and so the risk
actually was varied above that. That risk ratio is equivalent to an
incidence of 9.5 per 100,000. Full vaccination resulted in ten
additional cases of GBS in the cohort, compared to no vaccination,
pointing to roughly ten excess cases out of a million doses. This change
in GBS incidence resulted only in a small reduction in prevention of
QALYs lost: from 2,254 to 2,247. In other words, changes in the
attributable risk of GBS from vaccine result only in small changes in
the outcomes,and the model, as a whole, continues to strongly favor
vaccination.]{.mark}

[In summary, the estimated excess risk from VAERS remains unchanged in
analyses and so publication of these data are ongoing. The clinical
outcomes observed were typical, not substantially worse than reported in
the literature. Excess risk was comparable to that seen in some prior
seasonal influenza vaccines, and vaccination is favored, even with
larger magnitude of risk from the decision analysis. A large controlled
study being conducted by the Harvard Pilgrim Medical System to assess a
potential causal relationship between GBS and Menactra.]{.mark}

[]{.mark}

**[Immunogenicity and Safety of Menactra (MCV4) in 2- to 10-Year Old
Children]{.mark}**

[]{.mark}

[Dr. Gilmet presented the results of four large Menactra clinical trials
in children: a pivotal safety and immunogenicity single-dose comparative
study of Menactra versus Menomune; an immune-memory response study two
to three years after Menactra priming in young children ages two to
three years; an evaluation of boosting with Menactra in infants in the
U.K. who were previously primed with men-C conjugate vaccine; and a
large-scale safety study performed in the U.S. and Chile.]{.mark}

[The overall safety profile of Menactra compared to Menomune for
immediate, local, and solicited systemic reactions was very comparable.
Unlike adolescents, in whom local reactions were somewhat higher with
Menactra than Menomune, this was not the case in these two- to
ten-year-olds. No vaccine-associated serious adverse events were
reported in either study group. Most events reported were mild to
moderate in intensity. The percentage of vaccinees with localized pain
was nearly identical in the two groups, most solicited systemic
reactions were mild, with comparable percentages of fussiness,
drowsiness, and fever, and all events were reported to be transient in
nature.]{.mark}

[Regarding immunogenicity, when the geometric mean titers at Day 28 post
vaccination for Serogroup C were broken down by age, there was an
apparent increase in the immune response with increasing age, a
characteristic shared with other conjugate vaccines. Menactra responses
exceeded those of Menomune at all ages, often to a considerable
degree.]{.mark}

[Comparing the seroconversion rates of Menactra versus Menomune in two-
to ten-year-olds (seroconversion defined as individuals with titers less
than 1 to 8 at baseline who achieve a titer greater than or equal to 1
to 32 at Day 28 post vaccination), Menactra was statistically superior
to Menomune across all four vaccine-containing serogroups. There were
high seroconversion rates for both vaccines across the two-to-ten age
spectrum, but the performance of Menactra was better than that of
Menomune in the youngest age groups, and seroconversion rates were high
in the youngest children.]{.mark}

[Looking at geometric mean titers for Serogroup C at baseline, Day 28,
and six months post vaccination with Menactra versus Menomune, a
superior response is observed in Menactra at one month post vaccination,
which persists at six months.]{.mark}

[In summary, the Menactra safety profile was comparable to the Menomune
standard of care. Seroconversion rates were 86 to 99 percent in children
vaccinated with Menactra at Day 28. For all four serogroups, Menactra
produced significantly higher serum bactericidal antibody geometric mean
titers than did Menomune at Day 28, and the superior immune response
persisted out six months post vaccination.]{.mark}

[The recent broadened ACIP recommendation in 11- to 18-year-olds led to
an increased uptake of Menactra this past summer. However, supply has
been able to keep up with increased demand, and there is now a modest
surplus, which will continue to grow and permit consideration of further
program expansion in 2008 and beyond. The company is actively studying
Menactra in infants and toddlers, which presents a future opportunity to
more broadly immunize the population and replicate the recent success
seen in the U.K. and the Netherlands with men-C conjugate vaccination
programs.]{.mark}

[]{.mark}

**[Proposed Recommendations for Use of MCV4 in 2-10 Year Old Children at
Increased risk of Meningococcal Disease]{.mark}**

[]{.mark}

[Dr. Cohn noted that meningococcal disease causes 1400 to 2800 cases of
meningitis or sepsis per year in the United States. The case-fatality
rate is 10 to 15 percent, even with proper treatment. Ten to 20 percent
of survivors have permanent sequelae, such as limb loss, neurologic
disability, or hearing loss.]{.mark}

[Certain groups at increased risk for meningococcal disease have been
recommended to be routinely vaccinated with meningococcal vaccine. Among
two- to ten-year-olds, this includes children with functional or
anatomic asplenia, terminal complement deficiencies, and travelers to
areas where N. meningitidis is hyperendemic or epidemic. HIV-positive
children are likely at increased risk for meningococcal disease although
not to the extent that they are at risk for streptococcal infections.
Two- to ten-year-olds may be at increased risk for disease due to
organizational or communitywide outbreaks. There are about 70,000
persons with sickle cell anemia in the U.S., one of the primary causes
of functional asplenia. Only a fraction of these individuals are two to
ten years old. The incidence of asplenia is unknown. During 2001 to
2004, there were an estimated 1,000 children under 13 with HIV in the
U.S. So it is likely that no more than 20,000 doses of meningococcal
vaccine given to high-risk children in this age group in a given
year.]{.mark}

[Meningococcal polysaccharide vaccine is currently recommended for
persons two to ten years old and over 55, who are at increased risk of
meningococcal disease. This vaccine has been used since the 1970s and is
safe and effective in persons two years or older. However, bactericidal
antibodies titers drop two to three years after vaccination, especially
in young children.]{.mark}

[The quadrivalent meningococcal conjugate vaccine, MCV4. includes
polysaccharides for Serogroups A/C/Y/W-135, conjugated to 48 micrograms
of diphtheria toxoid. Conjugate vaccines elicit a T-cell dependent
response, which produces memory B-cells. Conjugate vaccines should
provide longer duration of protection than polysaccharide
vaccines.]{.mark}

[In the prelicensure clinical trial comparing MCV4 to MPSV4, all
subjects received four doses of DTaP prior to vaccination, and the mean
subject age was 3.7 years. Over 80 percent of subjects were between two
and five years old. For all serogroups at 28 days and six months, the
serum bactericidal antibodies titers, which are considered a correlate
of protection, were higher in the MCV4 group compared to MPSV4.]{.mark}

[Looking again at geometric mean titers at Day 28 post vaccination in
two- to ten-year-olds, the number of children in each single age year is
small, especially in the older age group. MCV4 is comparable or superior
to MPSV4 for each single age year. However, similar to MPSV4, SBA titers
increase with increasing age in MCV4-vaccinated children, with
maturation of the immune system. No single measure correlates to
long-term protection, but using boostability, there is not a substantial
difference in the magnitude of the immune response in two- to
three-year-olds between these two vaccines.]{.mark}

[The clinical trial also compared safety. There were no serious adverse
events in either group. Of the MCV4 reactions, 91.4 were mild or
moderate, and 98.8 percent of the reactions in MPSV4 recipients were
mild or moderate. All reactions resolved without sequelae, and MCV4
recipients experienced more severe local reactions than MPSV4
recipients.]{.mark}

[One additional study looked at booster responses of four- to
five-year-olds who were vaccinated at two to three years old with MCV4
and compared them to vaccine-naive children two or three years later.
All subjects received a challenge dose to one-tenth of a dose of MPSV4
to simulate exposure. SBA titers were tested at baseline and eight days
after MPSV4 challenge in the MCV4-primed and the MCV4-naive group. While
the numbers are small, for all serogroups, the MCV4-primed subjects had
significantly higher geometric mean titers than the vaccine-naive group.
A booster response was exhibited two to three years after vaccination
with MCV4. However, the titers at baseline two to three years after MCV4
vaccination are low, especially for Serogroup C.]{.mark}

[In summary, immunogenicity from MCV4 is noninferior in two- to
ten-year-olds compared to MPSV4. Safety profiles are similar. Two- to
three-year-olds have a booster response on challenge two to three years
after vaccination. The titers prior to the challenge are low. Most
children at increased risk for meningococcal disease are at lifelong
increased risk, which will make revaccination necessary.]{.mark}

[The meningococcal working group proposes recommendations for the use of
MCV4 in high-risk two- to ten-year-olds, with draft wording as follows:
*"For children two to ten years with increased risk of meningococcal
disease, MCV4 is preferable to MPSV4."* The following line would address
revaccination of children previously vaccinated with MPSV4. *"For
children two to ten years old who previously received MPSV4 and remain
at increased risk for meningococcal disease, ACIP recommends vaccination
with MCV4 three to five years after receipt of MPSV4."* Background rates
of Guillain-Barré syndrome are lower in two- to ten-year-olds compared
to older adolescents. The following precaution would be included in the
notice to readers. *"Persons with a history of GBS may be at increased
risk of GBS after MCV4. Therefore, a history of GBS is a precaution to
receiving MCV4." *]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Cieslak asked whether the immunogenicity studies were done in the
population with functional or anatomic asplenia or other high-risk
groups. Dr. Cohn said they were not.]{.mark}

[Dr. Craig asked whether neurologists were comfortable with the
diagnosis levels of Guillain-Barré syndrome. Dr. Clark responded that
the case definitions were still evolving, but the fact that the great
majority of cases were Level 2 or 1 seemed to be significant. Dr. Craig
said that if Level 2 were uncertain, then some cases might be Level 3,
and then there would be fewer GBS cases associated with this
vaccine.]{.mark}

[Dr. Iskander commented that in discussions of the use of the Brighton
collaboration case definition for the controlled study, the consulting
neurologist had the opposite concern and feared that requiring any level
might, in fact, exclude certain atypical presentations. Dr Baker thought
that the use of plasmapheresis and IVIG suggests that the people taking
care of these children are convinced that they have Guillain-Barré, even
though there may be misdiagnosed variants.]{.mark}

[Dr. Judson asked how the phrase "not substantially increased" should be
interpreted by clinicians or providers. Dr. Clark clarified that the
risk of GBS is not substantially increased. The current influenza
statement, for example, says that current estimates of the risks of
vaccine are not outweighed by the effects of disease. Dr. Baker noted
that people need to clearly understand the disease burden per 100,000
vaccinees vs. per million doses. Dr. Clark added that prior GBS is
listed as a precaution among all vaccine recipients, not just those at
high risk for disease.]{.mark}

[Dr. Lewis pointed out that the first statement, about children with
increased risks getting MCV4 preferably, begs the question of what
happens when that child turns 11. There needs to be some statement to
say whether or not they need to be vaccinated with the MCV4 again. Dr.
Cohn replied that it is not yet known if and when that child will need
to be revaccinated. There could be language such as "ACIP will provide
future recommendations." Dr. Lett felt the notice to readers should
specifically mention the risks and the benefits of vaccination.]{.mark}

[Dr. Katz asked how practioners would interpret the statment that
Guillain-Barré syndrome is a "precaution to receiving MCV, " as opposed
to a contraindication. Dr. Iskander clarified that precautions involve
situations in which the benefits may outweigh the risks, whereas in a
contraindication the risks always outweigh the benefits. The basis for
saying this was a precaution was that one of the original five cases
reported was a third episode of Guillain-Barré syndrome following
different vaccines, all with similar intervals.]{.mark}

[Dr. Halsley was bothered by estimates that only 50 percent of the
product distributed had been administered. Ten to 20 years ago, the
estimates of vaccine wastage were as low as 10 percent, maybe 20 percent
for the traditional low-cost vaccines. He suggested that the data be
refined before publication to avoid creating false impressions about the
potential rates or risk ratios. Dr. Wallace agreed, but noted that with
some of the new adolescent vaccines, there was a tendency to over-buy in
the beginning and that rates improve over time. Dr. Clark added that
analyses done through ISO allow at least more than the 42-week risk
window for cases to occur and be reported and doses not to sit on the
shelf, so there is really a two-month delay in reporting of
rates.]{.mark}

[Dr. Plotkin asked if the working group considered induction of
tolerance as another reason for preferring the conjugate vaccine. Dr.
Baker replied that there had been a fairly robust review of the
literature on tolerance and the polysaccharide vaccines due to mening.
Dr. Stephens added that the issue was not necessarily tolerance, but
rather hypo-responsiveness. There is responsiveness with multiple doses
of polysaccharide, but less with repeated doses. However, the data still
suggest protection with the polysaccharide. Dr. Cohn pointed out that
studies have shown the polysaccharide vaccine continues to be effective
in high-risk individuals with terminal complement deficiencies.]{.mark}

[Dr. Pickering asked about the statement that bactericidal titers drop
at two to three years. Dr. Gilmet's presentation showed that at six
months antibodies titers were still significantly different, but very
low. He wondered if the assumption was that titers after two to three
years for both vaccines are fairly similar and that the real benefit in
this age group would be the immunological memory or lack of tolerance.
Dr. Cohn replied that titers had not yet been reviewed sufficiently for
MCV4, but that the boostability data are supportive of MCV4 providing a
longer duration of protection than MPSV4.]{.mark}

[Dr. Duchin asked whether the wording for the precaution regarding
administration of Menactra to persons with a history of GBS was based on
a single case. Dr. Iskander replied that it had more to do with ACIP
influenza vaccine wording. In the manufacturer\'s package insert, GBS is
listed as a contraindication, but CDC wants to keep it as a precaution.
Dr. Duchin asked if the committee could provide some background on what
is known about immunization among people who have a prior history of
GBS. Dr. Iskander replied that the Clinical Immunization Safety
Assessment network was currently moving forward with a protocol to
accumulate clinical information on those cases.]{.mark}

[Dr. Cohn then reviewed the proposed recommendation*: "For children two
to ten years old with increased risk of meningococcal disease, MCV4 is
preferable to MPSV4. *]{.mark}

*[For children two to ten years old who previously received MPSV4 and
remain at increased risk for disease, ACIP recommends vaccination with
MCV4 three to five years after receipt of MPSV4. Persons with a history
of GBS may be at increased risk of GBS after MCV4. Therefore, a history
of GBS is a precaution to receiving and MCV4."]{.mark}*

[She proposed adding "*No vaccine provides lifelong protection.
Therefore, revaccination will likely be necessary. ACIP will provide
recommendations for revaccination when more data on duration of
protection becomes available." *]{.mark}

[Dr. Baker suggested saying "*No conjugate vaccine provides lifelong
protection."*]{.mark}

[Dr. Neuzil moved that the committee vote on the proposed language. Dr.
Baker seconded the motion.]{.mark}

[ Dr. Judson said he assumed there still was not an understanding of how
to interpret the declining geometric mean titers in terms of efficacy.
Because meningococcal disease has a short incubation time, there may not
be the same effect as when there is time for an anamnestic response to
occur with boosting. If the recommendation is re-vaccination three to
five years after receipt, ACIP would be erring on the side of caution
without any real supporting data.]{.mark}

[Dr. Baker suggested it would be clearer to recommend immunization after
three years, rather than three to five years. Dr. Decker noted that the
current recommendations call for these children to receive
polysaccharide vaccine every three to five years, but clinicians will
inevitably ask whether children who previously got the polysaccharide
should now get the conjugate.]{.mark}

[Dr. Chilton asked whether there were any data on what happens when
children get multiple doses of conjugate vaccine. Dr. Cohn replied that
the working group had not yet reviewed data on second doses of conjugate
vaccine. Dr. Baker clarified that there are data on the polysaccharide,
but that data on durability of the conjugate in a variety of situations
are not yet available.]{.mark}

[Dr. Cohn then suggested the following wording: "*No conjugate vaccine
provides lifelong protection. Therefore, revaccination will likely be
necessary, and ACIP will provide recommendations for revaccination when
more data on duration of protection become available." *]{.mark}

[Dr. Decker wondered if would be better to say "bacterial" rather than
"conjugate", since many viral vaccines are believed to give lifelong
protection. Dr. Orenstein remarked that since ACIP does not recommend
revaccination for any conjugate vaccine right now, it would better to
say the duration of protection is not known. The ACIP will continue to
evaluate and will make recommendations for revaccination, should it be
necessary. Dr. Cohn agreed, but pointed out that children at high risk
will continue to be so for life and that revaccination will be different
for this group than for children who are just at increased risk for a
certain period of time. Dr. Cohn suggested removing the language "*No
conjugate vaccine provides lifelong protection. Therefore, revaccination
will likely be necessary".*]{.mark}

[Dr. Salisbury noted that no breakthrough meningococcal disease has been
seen the U.K. childhood population that was vaccinated in 1999-2000,
albeit just with a meningococcal C conjugate. Meanwhile, there is
probably remarkably little transmission, so they may not be exposed to
risk, but the catch-up done probably displaced the meningococcal
C.]{.mark}

[Dr. Lewis expressed concern about what happens to an eleven-year-old
who got MCV4 at age nine without any guidance about revaccination. Dr.
Messonier said that the context for today's vote was an exceedingly
small group of very specific two- to ten-year-olds who are at high risk
because they do not have spleens. Discussion of the larger issues will
be continued in February. Dr. Baker pointed out that the most recent
adolescent statement says "All adolescents not previously
vaccinated."]{.mark}

[Dr. Decker noted that the antibody levels produced by Menactra are very
comparable, age by age, to those produced by the U.K.-licensed mening C
vaccines, with similar durations of antibody. The big difference is
hitting the whole population at once versus doing it
incrementally.]{.mark}

[Dr. Morse asked the committee to vote on the motion on the floor to
accept the proposed recommendations minus the first bullet on the
revaccination.]{.mark}

[Dr. Englund; abstain.]{.mark}

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

[Dr. Craig; yes.]{.mark}

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

[Dr. Judson; yes.]{.mark}

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

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

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

[Dr. Chilton; yes.]{.mark}

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

[Dr. Cieslak; yes.]{.mark}

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

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

[Dr. Hull; abstain.]{.mark}

[The motion passed with two abstentions.]{.mark}

[]{.mark}

[Dr. Wallace presented the VFC recommendation for a vote. He explained
that the purpose of the resolution was to add the expanded age
indication just discussed. Under the polysaccharide vaccine, an eligible
group was added and those who may have a precaution or a
contraindication for the conjugate vaccine were included.]{.mark}

[For the conjugate vaccine, the priority for certain ages based on
supply was removed since that issue is resolving. For the high-risk
groups, 'adolescents' has been changed 'children and adolescents' and
age has been lowered to two years. There is still the routine
recommendation for ages 11 to 12, as well as those who are 13 to 18 and
have not been previously vaccinated. For the recommended schedule, it
has been lowered to two years of age. In some instances, if the
polysaccharide has been given previously, revaccination is recommended.
Currently the conjugate vaccine is only a single-dose
recommendation.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Judson asked whether the recommendation should say N. meningitides
or meningococcal disease. N. meningitidis is really endemic or
hyperendemic in many populations that do not experience high rates of
disease. Dr. Messennier agreed that the sentence that says "in countries
where Niceria meningitidis is endemic or epidemic" should say
"meningococcal disease". Dr. Wallace said the recommendation targeted
people going to countries, predominantly in Africa, that have high rates
of disease and that a change could be made. Dr. Decker asked whether the
vaccination was given only if the country currently has an outbreak. Dr.
Schuchat explained that the meningitis belt of Africa is always
included. Other areas that are having outbreaks would also be
added.]{.mark}

[]{.mark}

[Dr. Craig moved approval of the recommendation and Ms. Stinchfield
seconded the motion.]{.mark}

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

[Dr. Judson; yes.]{.mark}

[Dr. Lieu ; yes.]{.mark}

[Dr. Craig; yes.]{.mark}

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

[Dr. Englund; abstain.]{.mark}

[Dr. Hull; abstain.]{.mark}

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

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

[Dr. Cieslak; yes.]{.mark}

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

[Dr. Chilton; yes.]{.mark}

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

[Dr. Morse; yes. The motion passed with two abstentions.]{.mark}

[]{.mark}

**[Considerations for Routine Use of MCV4 in 2-10 Year Old
Children]{.mark}**

[]{.mark}

[Dr. Cohn presented some issues the working group has been discussing
around routine use of MCV4 in two- to ten-year-olds, to prepare for an
ACIP vote in February 2008. They included the burden of disease in two-
to ten-year-olds, duration of protection provided by MCV4, and
programmatic considerations for vaccination in the two- to ten-year-old
age group.]{.mark}

[The national passive surveillance system known as NETTS receives case
reports from all 50 states. A graph of the incidence of meningococcal
disease in the United States from 1970 to 2005 shows a cyclical waxing
and waning pattern, with peaks typically every eight to ten years. The
case-fatality rate decreased in the 1970s, but has remained stable at
around 10 percent since the 1980s.]{.mark}

[ABCS is an active laboratory and population-based surveillance system
composed of ten geographically dispersed sites. Excluding Oregon, which
had an ongoing Serogroup B disease outbreak and higher rates of disease
than in other states, since 1996 incidence of meningococcal disease has
been on a downward cycle. Serogroups B, C, and Y each cause
approximately one-third of meningococcal disease in the United States.
The incidence of Serogroup C and Y, which are contained in MCV4, have
decreased more than Serogroup B and since 2002, Serogroup B disease has
caused the highest disease incidence. There is currently no vaccine
available for Serogroup B.]{.mark}

[There are two peaks of meningococcal disease among children and
adolescents: one in infancy and early childhood and the second in late
adolescence. The 11- to 12-year-olds routine MCV4 recommendation
targeted that adolescence rise. Disease rates in two-year-olds are
around 1 per 100,000, the same as in 18- to 19-year-olds. However, rates
drop quickly after age two and overall rates among two- to ten-year-olds
are lower than in 11- to 19-year-olds.]{.mark}

[Fifty-four percent of cases of meningococcal disease are vaccine
preventable in two- to four-year-olds, through either Serogroup A, C, Y,
or W-135, compared to 75 percent of cases among 11- to 19-year-olds. The
case-fatality rate in young children, while still higher than other
infectious diseases, is lower than in older age groups. The case
fatality rate is five percent for two- to four-year-olds and ten percent
among five- to ten-year-olds.]{.mark}

[Excluding serogroup B and based on a small number of cases, there are
an estimated 160 potentially vaccine-preventable cases among two- to
ten-year-olds per year in the U.S, which is about one-third fewer than
among 11- to 19-years-old. The same number occurs among a much smaller
cohort of children less than two years old. The burden of disease in
two- to ten-year-olds is relatively lower than in other age groups, and
25 percent of disease is in two-year-olds alone. A lower proportion of
disease among two- to ten-year-olds is vaccine preventable compared to
older age groups.]{.mark}

[Unlike other causes of bacterial meningitis, meningococcal disease has
a second peak in risk in late adolescence and therefore requires longer
protection. Conjugate vaccines should have a longer duration of
protection than polysaccharide vaccine, given that serum bactericidal
antibody titers in the younger children receiving MCV4 were not
substantially higher than in children who received MPSV4. The working
group fears a single dose in two-year-olds will not provide protection
through late adolescence. There are no routine vaccines currently
recommended at the two-year-old visit. Several vaccines are recommended
in four- to six-year-olds, but the timing of this vaccination visit is
after the elevated disease risk in this age group. The 2006 National
Immunization Survey Teen Module showed MCV4 coverage was only 11.7
percent among 13- to 17-year-olds, which is not surprising given the
short time between the recommendation and the survey.]{.mark}

[In summary, the meningococcal working group continues to evaluate data
on the use of MCV4 in two- to ten-year-olds. Vaccinating captures only
the cusp of increased disease in infants and toddlers. A safe and
effective vaccine given in younger infants or toddlers would have more
impact on disease burden. Duration of protection is unknown. An infant
or toddler vaccine that would protect through late adolescence is ideal,
but more likely, revaccination will be necessary. Implementation of a
vaccine recommendation in this age group may be challenging because the
only established vaccination visit is at four to six years old, not the
ideal time for vaccination based on burden of disease.]{.mark}

[The working group has a wide range of opinions on the option of a
permissive statement for vaccination of two- to ten-year-olds. FDA
licensure is already permissive. A permissive recommendation from ACIP
would have implications for insurance reimbursement and VFC coverage. It
may cause confusion, but would ensure provider and parent choice. The
group is planning to present recommendations on routine use of MCV4 in
two- to ten-year-olds at the February 2008 ACIP meeting and ask for a
vote at that time. Vaccines for infants and young toddlers may be
available in the United States in the near future and Serogroup B
vaccines are in development.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Neuzil was curious to know the definition of "the near future,"
regarding vaccines for infants and young toddlers. Dr. Friedland
reported that GlaxoSmithKline was currently in Phase III development for
an infant vaccine with meningococcal Serogroups C and Y in combination
with Hib vaccine. Dr. Bann said that Novartis Vaccines was also in Phase
III trials with an infant A/C/Y/W-135 conjugate vaccine. Dr. Decker from
sanofi pasteur commented that no manufacturers were willing to predict
when FDA will license something, however, two years seems a little
optimistic and five years would be sadly pessimistic. His company
presented its infant-toddler clinical trial results to the working
group, and expects to present more data.]{.mark}

[Dr. Morse asked if there was information on carriage rates in the two-
to ten-year-old age group versus the adolescent group, and whether they
might serve as a reservoir. Dr. Cohn replied that studies suggest
carriage is actually higher in adolescents than in younger
children.]{.mark}

[Dr. Lieu felt that a decision might revolve around the projected
benefits vs. projected costs. When the committee voted on meningococcal
conjugate vaccine for adolescents, it already was one of the vaccines
with the highest cost-effectiveness ratios, i.e., the most costly for
quality-adjusted life-year saved. If the incidence of disease is lower
in two- to ten-year-olds and a booster will probably be required
downstream, it would be interesting to hear about plans for analysis of
that issue before coming to a vote. She added that the question of how
quickly immunity wanes was really crucial and where those assumptions
come from would be very important in sensitivity analyses.]{.mark}

[Dr. Hull asked whether recommending a vaccine at age two would require
an additional visit. Dr. Bocchini of the AAP said there was already a
routine two-year-old visit recommended, but no routine immunizations are
given at that time. Dr. Chilton said that New Mexico experienced a
marked drop-off in completion of immunizations after one year of age.
However, of those who continue to be seen, a large proportion is seen at
age two and there are recommendations for other preventive care at age
two. Dr. Grogg added that people tend to come in if there is a vaccine
to be given, so he encouraged the use of vaccination for screening
purposes. A lot of important things, such as speech, are picked up at
age two.]{.mark}

[Dr. Lewis said that a study of health-plan patients, specifically
around 15-month vaccine recommendations, found that about 70 to 80
percent attended the one-year visit and nine percent came to a 15-month
visit.]{.mark}

[ ]{.mark}

[]{.mark}

**[Childhood and Adolescent Immunization Schedule]{.mark}**

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

[]{.mark}

[Dr. Calugar presented the final draft immunization schedule for persons
aged zero through 18 years for the year 2008. The process for updating
the schedule included collecting data from immunization providers,
summarizing data from NIP Info, presenting the working group's comments
and suggestions to subject-matter experts, and presentation of a
preliminary draft to ACIP in June, with a vote in October. There might
be some additional work on the immunization schedules' charts and
footnote pending the ACIP vote on updated and/or new recommendations
presented by other ACIP WGs during the October meeting. On the schedule,
yellow bars denote the range of recommended ages, green bars represent
catch-up immunization and purple bars are designated for high-risk
groups.]{.mark}

[Changes to the schedule for ages zero through six years include the
following: There will be no green catch-up bars for hepatitis B and Hib
vaccines, because providers found it confusing having catch-up
recommendation in the routine schedules. However, a new line was
incorporated at the top of the page: *"For those who fall behind or
start late, see the catch-up schedule."* There is no PCV purple bar for
two- to five-year-olds and only the PPV purple bar remained; this should
eliminate confusion expressed by providers about pneumococcal
vaccination in high-risk groups. In anticipation of the new MCV4
recommendations, MPSV4 was changed to mening-conjugate vaccine, MCV4,
for the two- to six-year-olds, with a purple bar for high risk. Finally,
there is additional wording under the chart: *"Providers should consult
the respective ACIP statement for detailed recommendations including for
high-risk conditions."* The referenced URL takes readers to the ACIP Web
page with all the resources.]{.mark}

[Regarding the footnotes for this age group, for the hepatitis B
birth-dose paragraph, the last bullet reads, *"If mother is HBs-AG
negative, the birth dose can be delayed in rare cases with provider's
order and a copy of the mother's negative HBs-AG laboratory reports in
the infant\'s medical record."* PCV now reads, *"At ages 24 through 59
months, administer one dose of PCV to incompletely vaccinated healthy
children and two doses of PCV at least eight weeks apart to incompletely
vaccinated children with certain high-risk conditions. Administer PPV
for children age two years and older with certain high-risk
conditions."* For the mening vaccine, the footnote says, *"Administer
MCV4 to children aged two to ten years with terminal complement
deficiencies or anatomic or functional asplenia and to certain other
high-risk groups. Use of MPSV4 is also acceptable." *]{.mark}

[The influenza footnote required extensive revision related mainly to
FluMist. Minimum age now starts with two-year-olds, and the minimum
interval between the doses is four weeks; previously, it was six weeks.
Overall, there are five bullets on the influenza vaccine for ages zero
through six years. First, "*Administer annually for children aged 6
through 59 months and to close contacts of children aged zero through 59
months*. Second, "*Administer annually to children five years of age and
older with certain risk factors and to other persons, including
household members in close contact with persons in groups at higher
risk, and to any child whose parents request vaccination."* Third, *"For
healthy persons, those who do not have underlying medical conditions
that predispose them to influenza complications, ages 2 through 49
years, either LAIV or TIV may be used."* Fourth, "*Children receiving
TIV should receive 0.25 mL if aged 6 through 35 months or 0.5 ml if age
three years or older."* And finally, *"Administer two doses separated by
four weeks or longer to children younger than nine years who are
receiving influenza vaccine for the first time or who were vaccinated
for the first time last season, but only received one dose."*]{.mark}

[The proposed schedule for ages 7 through 18 years also has the new
sentence in the title, *"For those who fall behind or start late, see
the catch-up schedule."* Ages 13 through 18 are combined in one column.
For mening vaccine, 11- to 12-year-olds are covered by the routine
immunization (yellow bars) and 15 through 18 years by catch-up green
bars. This makes Menactra\'s presentation in the schedule similar to
Tdap and HPV series. In addition, the purple bar for seven- to
ten-year-olds now has MCV instead of MPSV4. And finally, under the
immunization chart, the ACIP URL has been incorporated.]{.mark}

[Proposed footnotes for ages 7 through 18 years included changes to
mening and influenza vaccines. Meningococcal vaccine says: *"Administer
MCV4 at ages 11 to 12 years and age 13 through 18 years if not
previously vaccinated. Administer MCV4 to previously unvaccinated
college freshmen living in dormitories. MPSV4 is an acceptable
alternative."* For influenza vaccine, the footnote was reworded for
clarity and consistency with the updated recommendations for zero
through six-year-olds.]{.mark}

[The current catch-up schedule is split in two age groups, ages four
months through six years at the top and 7 to 18 years at the bottom.
There was an error for the TD/TDaP ages 7 to 18 years. Under Column Dose
2 to Dose 3, it should say four weeks.]{.mark}

[Changes to the catch-up footnotes are consistent with the routine
schedule for ages zero through six and 7 through 18 years, such as
updates for pneumococcal conjugate vaccine, PCV. The new wording is:
"*At ages 24 through 59 months, administer one dose of PCV to
incompletely vaccinated healthy children and two doses of PCV at least
eight weeks apart to incompletely vaccinated children with certain
high-risk conditions."* The following sentence was deleted: "*PCV is not
generally recommended for children aged five years and older,"* after
consulting with the subject-matter experts. For inactivated polio virus
vaccine, IPV, a new sentence was added as a stand-alone bullet: "*IPV is
not generally recommended for persons aged 18 years and older."
*]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Chilton noted that the draft still did not say what to do with a
child who has received two doses of influenza vaccine previously in
separate years. Dr. Neuzil responded that ACIP voted last year to
harmonize with the AAP recommendation that if a child had a single dose,
then the following year, he or she should get two doses. Dr. Wallace
added that if a child only gets one dose the first year and one dose the
second year, ACIP is not recommending two doses the third year. Dr.
Atkinson provided additional clarification, in that he had been saying
publicly that if a child got one dose, skipped a year and then came back
the following year, that two doses were indicated, but that is not true.
The two-dose rule is only applicable in either the first or the
chronologic subsequent year. So if a child got one dose one year and one
dose the next year, it is still only one dose from the third year
forward.]{.mark}

[Dr. Campos-Outcalt thought it was simpler to say that any child under
age nine who has not had two previous doses needs two doses. Dr. Wallace
explained that these recommendations had been made by the influenza
working group and that any changes in wording would have to be done by
that group.]{.mark}

[Dr. Judson pointed out that a number of situations had no long-term
immunogenicity and efficacy data for different dosing regimens. He asked
whether the immunogenicity and efficacy data were supportive of the last
statement. Dr. Neuzil explained that the main point made in the working
group was that if children are younger than nine, they need two doses
the first year they receive vaccine. Seventy percent of young children
are not getting any flu vaccine. If people are still confused, the
working group can work on it.]{.mark}

[Dr. Cieslak asked whether a 12-month-old was supposed to be given DTaP,
and whether there was any reason that the bar does not go back to 12
months. Dr. Wallace explained that the wording reflected the ACIP
recommendations, which say the time to give it is 15 to 18 months, but
then adds the compromise language. Dr. Calugar added that providers
should be reading the footnotes when they have additional questions.
When working on the immunization schedule, the ACIP WG was considering
only published recommendations or preliminary ones that were voted by
the ACIP and posted on the ACIP Web site but not yet published in the
MMWR.]{.mark}

[Dr. Campos-Outcalt asked what the potential consequences might be of
disseminating ACIP recommendations that have not yet appeared in an
*MMWR*. Dr. Calugar replied that publication of all ACIP recommendations
in the *MMWR* is a lengthy process and some are followed by the vote on
the VFC resolution as well. Dr. Campos-Outcalt suggested noting that
these were preliminary recommendations on the schedule. Dr. Schuchat
noted that the more important issue was that the child, adolescent, and
adult schedules are updated every year. In general, timing of final
publication in *MMWR* is slow and unpredictable, but the provisional
recommendations need to correspond with VFC votes and complete
information needs to get out as quickly as possible to programs,
practitioners, and insurance plans.]{.mark}

[Dr. Whitley-Williams suggested adding a statement in the schedule about
revaccination, particularly under MCV4. There is now a cohort that has
been immunized and is approaching college years.]{.mark}

[Dr. Duchin asked if it was possible to say recommendations were
"approved and voted on but not yet published", because "provisional"
gives the impression that they are liable to be changed prior to
publication. Dr. Pickering explained that approval of recommendations is
a four-stage process, involving a lot of clearance. Now it takes nine
months or more, but a method for shortening the process is being
investigated. However, the provisional recommendations are posted and
are rarely changed, except for minor wording. The ACIP is an advisory
committee and CDC has to give the acceptance, which requires clearance.
Dr. Schuchat added that the ACIP is the sole authority for inclusion of
a vaccine in the Vaccines for Children program and the decision is
active the day of the vote.]{.mark}

[Dr. Tan noted that the difference in timing between the provisional
recommendations from ACIP and the publication in *MMWR* causes payment
delays for private physicians.]{.mark}

[Dr. Lewis noted that the DTaP fourth dose had a specific recommendation
for 15 months, but that the fourth dose on all of the CPT or HEDUS rates
is consistently the one that drops off. One of the biggest issues is not
having it at 12 months and making that not look permissive.]{.mark}

[Dr. Wexler expressed concern about the hepatitis B catch-up bar
dropping off for the 19-month to six-year-olds, because there is no
longer an indication that zero to 18-year-olds should be vaccinated.
That used to be in the footnotes, but there\'s no green bar that serves
as a reminder. The catch-up table often isn\'t reproduced when the
schedule is reproduced. Dr. Calugar explained that immunization
providers in the field had found the green bars confusing and that the
fewer colors there were on the schedule, the more they could focus on
routine immunization. However, there is a permanent reminder at the top
of the page for those who fall behind or start late to see the catch-up
schedule.]{.mark}

[Dr. Wexler's second concern was about the permissive recommendation for
influenza and hepatitis A. Hepatitis A vaccine can be given to any child
up the age 18, and it should be considered, and influenza can be given
to any child up through age 18.]{.mark}

[However, there is no indication on the table that these are permissive
recommendations. It looks like it is only for high-risk people and many
people might be advised that it is not recommended for them. Dr. Calugar
pointed out that the current schedule's footnote says that hepatitis A
is recommended for all children aged one year. The two doses in the
series should be administered at least six months apart. Children not
fully vaccinated by age two can be vaccinated at subsequent visits.
Hepatitis A is recommended for other groups of children, including in
areas where vaccination programs target all the children. It is as
inclusive as possible and it corresponds with the current published
recommendation. It is not possible to override the existing *MMWR*, but
it can be discussed in the working group for next year's
schedule.]{.mark}

[Dr. Plotkin asked about the import and basis of the statement that IPV
is not generally recommended after the age of 18 in the catch-up
schedule. Dr. Calugar explained that it reflected the package insert.
Dr. Plotkin noted that it was probably an historical remnant from the
Red Book that may still apply to OPV, but does not apply to IPV. He
asked whether a 19-year-old going to Northern Nigeria should have IPV.
Dr. Wallace replied that this was not a travel recommendation. Dr.
Plotkin then asked whether an Amish person who hasn\'t had polio vaccine
before could have IPV. Dr. Wallace clarified that there was not a
routine recommendation that all 18-year-olds and older should be getting
IPV. Dr. Hull suggested saying that it is not routinely recommended, but
would be permitted in infrequent cases. Dr. Wallace said that extensive
word-smithing could eventually be a problem in terms of harmonizing with
AAP and AAFP. He said he would be fine with getting rid of the IPV
statement all together. Dr. Pickering clarified that in The Red Book,
the AAP only deals with those up to 18 years of age, but there is a
section on vaccine recommendations for adults that says IPV can be
given.]{.mark}

[Ms. Johammer from the California Department of Health Services
Immunization Branch said the Web site links on the schedules were not
terribly helpful. Most people just refer to the schedule displayed on
their walls, so it would be more helpful to have a simple Web site
address like [www.cdc.nip](http://www.cdc.nip/), which people could
remember.]{.mark}

[Dr. Morse asked if there was a motion to approve the schedule. Dr.
Baker so moved and Dr. Chilton seconded the motion, as did Dr.
Morita.]{.mark}

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

[Dr. Chilton; yes.]{.mark}

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

[Dr. Cieslak; yes.]{.mark}

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

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

[Dr. Hull: If I can vote, yes. Otherwise, abstain.]{.mark}

[Dr. Englund; yes.]{.mark}

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

[Dr. Craig; yes.]{.mark}

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

[Dr. Judson; yes.]{.mark}

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

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

[]{.mark}

**Combination Vaccines**

**Ms. Patsy Stinchfield, ACIP WG Chair**

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

**Dr. Wayde M. Weston, GSK**

**Update: Combination Vaccines Working Group**

Ms. Stinchfield explained that the working group had reviewed two new
products. The BLA for Sanofi Pasteur's Pentacel four-dose primary series
has been done, but FDA requested additional information, which resulted
in an extension of the review clock. Kinrix, the GlaxoSmithKline
biological, was reviewed in anticipation FDA licensure.

The group plans to revise the 1999 *MMWR* statement on the use of
combination vaccines for discussion and approval by the ACIP. One of the
statements under review says, "*Combination vaccines should be used to
minimize the number of injections children receive, and are practical
for starting immunization series for children who are behind schedule."*
Other issues include when extra doses would be justified, the benefits
and risks of administering the combination vaccine with an unneeded
antigen, including the reactogenicity of the inactivated vaccine, the
interchangeability of formulations and of vaccines from different
manufacturers and the impact on reimbursement policies. There are also
monitoring issues, such as safety, efficacy, and coverage.

The group will look at the impact of using combination vaccines on the
immunization schedule and potential programmatic, administrative, and
financial burdens on private providers in the current vaccine market. It
will review the issue of expressing the level of preference of
combination vaccines versus single-antigen ones and identify any
circumstances when single-antigen vaccines should be strongly
considered, considered, or preferred.

**Impact of Combination Vaccines**

Dr. Wallace said that a child gets 34 to 36 injections through age five
or six years of age and then showed the CDC series costs and the
private-sector costs, which is really a catalog cost. Comvax decreases
the number of injections by two, but not the price, and when adhering to
the birth dose of hepatitis B, there is an extra dose of this antigen.
Using TriHibit for the fourth dose reduces the number of shots in the
series by one. For Pediarix, DTaP/HepB/IPV, there is a greater reduction
in the number of shots and a modest increase in price. ProQuad, which
currently is not available on the market, but is a licensed vaccine,
also decreases the number of shots by two with the new recommendation
for varicella vaccine, and the price is comparable. If approved,
Pentacel will provide the greatest decrease in the number of shots, but
there is an additional IPV dose; price is not yet known. Pediarix and
Kinrix would also decrease the number of shots and this combination has
the same additional HepB that Pediarix has on its own.

Dr. Wallace then discussed the distribution of doses since 2000 and the
market impact. Some shortages were not captured by the annual data
presented. When the new combination vaccine, Pediarix, was introduced,
the total DTaP market increased, but then as the new combination vaccine
gradually increased its market share, the others decreased. There was
quite a bit of sequential catch-up with hepatitis B, but as the Pediarix
market increased, the Comvax market went down. The same trend was seen
in the IPV market. The monovalent Hib vaccine market share actually went
up when Pediarix was introduced. Even though Pediarix does not have Hib,
it displaced some of Comvax market. MMRV was introduced in 2006,
coinciding with the new two-dose recommendation; there is currently a
shortage, but it is expected to come back. MMR, having more of a market
share than just the pediatric indication, initially went down with MMRV,
while varicella stayed stable.

In conclusion, combination vaccines decrease the number of required
shots, but do not markedly increase the total vaccine cost. Other costs
may occur, such as storage, reimbursement or administration, however
there may also be opportunity costs. Changing markets are dynamic and
somewhat unpredictable and can be influenced by a number of factors.
Combination vaccines may complicate schedules, particularly for
catch-up; registries can be very useful for that. On the other hand,
combination vaccines may improve coverage and this needs more
quantitative data. They may lead to some extra doses, which should not
be an issue. Finally, combination vaccines can complicate targeting and
maintaining pediatric vaccine stockpiles.

**Immunogenicity and Safety of Kinrix (Combination DTaP-IPV Vaccine) in
Children 4-6 Years of Age**

Dr. Weston from GlaxoSmithKline explained that Kinrix received its first
global licensure in 1996 in France and is currently licensed in 31
countries worldwide. A BLA application was filed on April 6th, 2007.
Kinrix is intended for use as a fifth dose of DTaP vaccine and fourth
dose of IPV in children four to six years of age. Current
recommendations are for up to five vaccinations to be given to children
in this age group; DTaP and IPV account for two of these. Combining DTaP
and IPV vaccines into a single vaccine reduces by one the number of
injections required to provide the recommended immunizations to this age
group and should increase overall coverage and timeliness. The DTaP
antigen components of Kinrix are identical to those of GSK\'s Infanrix
and Pediarix vaccines in the same quantities and the IPV components are
identical to those of Pediarix in the same quantities.

The pivotal Phase III Study 048 was conducted in the U.S. in 2005-2006.
It included more than 4,000 children, over 3,000 of whom received Kinrix
as the study vaccine. Primary objectives included assessments of safety
and immunogenicity as well as manufacturing lot consistency.
Immunogenicity and safety were also investigated in a Phase II Study 047
in 2003 and 2004. This study provided information on the immunogenicity
of a co-administered MMR vaccine. Additional safety information comes
from a small Phase II study conducted in Australia, Study 046. Subjects
in all studies were healthy children four to six years of age, who had
had four prior doses of Infanrix and three doses of IPOL vaccine in
their first two years of life. They were randomized to receive either
one of three manufacturing lots of Kinrix or separately administered
Infanrix and IPOL vaccines. All subjects also received concomitant MMR
vaccination according to age-specific recommendation.

The study was open label with regard to combination or separate vaccine
receipt. The lot assignment for Kinrix was given double-blind. Safety
and reactogenicity assessments were conducted on all subjects in Study
048. Immunogenicity assessments were conducted on a subset of study
subjects whose parents agreed to have their children provide blood
samples. All subjects received vaccinations on designated Day 0. They
were then contacted by phone four to six days after vaccination to
collect reactogenicity observations. Subjects who were participating in
the immunogenicity analysis had a second study visit one month after
vaccination for collection of blood samples and safety information.
Subjects who were not part of the immunogenicity analysis got only a
phone contact to collect safety information. Finally, all subjects were
contacted by phone approximately six months after vaccination to collect
long-term safety information.

The primary objectives were to demonstrate non-inferiority of Kinrix to
Infanrix given with IPOL with respect to booster responses to DTaP
antigens and post-vaccination geometric mean titers for IPV antigens. In
addition, Study 048 included a consistency comparison of the three
manufacturing lots of Kinrix used. Secondary objectives were evaluation
of booster responses and post-vaccination antibody concentrations or
titers for all Kinrix antigens compared to Infanrix and IPOL, as well as
evaluation of immunogenicity of the MMR vaccine co-administered with
Kinrix compared to co-administration with Infanrix and IPOL in the Phase
II 047 study.

For safety, in the Phase III 048 trial the primary objective was to
determine non-inferiority of Kinrix to the Infanrix plus IPOL
combination with respect to increased circumferential swelling at the
DTaP injection site. Secondary objectives in all studies were evaluation
of safety and reactogenicity in terms of solicited local events, i.e.,
injection-site pain, swelling, redness, and increased arm circumference;
solicited general events, that is, fever, drowsiness, and loss of
appetite; unsolicited adverse events and SAEs.

Demographic data from the Phase III 048 study show that all treatment
groups were similar to each other and to the total study population in
terms of sex, racial and ethnic characteristics, and age. All study
objectives with respect to lot consistency were achieved.

Data were presented on serum antibody concentrations for anti-D and
anti-T antibodies and percentages of subjects with antibody
concentrations greater than or equal to one, which represents a
seroprotective level. Serum GMCs increased many-fold following
vaccination and proportions of subjects with antibody values exceeding
the cutoffs given approached 100 percent following vaccination with
either Kinrix or separately administered Infanrix and IPOL. Serum GMCs
for pertussis toxoid, filamentous hemagglutinin, and pertactin increased
many-fold following vaccination with either vaccine.

The primary immunogenicity comparisons for the diphtheria, tetanus, and
pertussis components of the vaccine were based on booster responses.
Both study groups showed a high booster response rate for both D and T
antigens. Both treatment groups also showed high booster response rates
for all pertussis antigens.

Looking at the non-inferiority comparisons for DTaP booster responses,
the between-group difference and percentage of subjects with booster
responses were determined for each vaccine component. Non-inferiority
was defined as the upper limit of the 95 percent confidence interval for
the treatment difference being less than or equal to 10 percent. That
criterion was met for all DTaP antigens.

Focusing on polio virus responses, Dr. Weston showed the increases in
percentages of subjects with seroprotective levels (titers of one to
eight or greater) of anti-poliovirus Types 1, 2, or 3 antibodies. Most
subjects had seroprotective levels of one or more antibodies prior to
vaccination. Following vaccination, all subjects were seroprotected for
all three poliovirus types except for a single subject in the Kinrix
group who was not seroprotected for Type 1 poliovirus. Antibody titers
for anti-poliovirus were similar prior to vaccination and increased
many-fold following vaccination. For the non-inferiority comparison for
poliovirus GMTs, the upper limit of the 95 percent confidence interval
for all three ratios was less than the predefined limit of 1.5, so the
study was also able to conclude non-inferiority of Kinrix to IPOL with
respect to immunogenicity of the poliovirus components.

The immunogenicity of co-administered MMR vaccine with either Kinrix or
separately administered Infanrix and IPOL vaccines was examined in the
Phase II Study 047. Reverse cumulative concentration curves were
determined for measles, mumps, and rubella antibodies when vaccine was
co-administered with either Kinrix or separate Infanrix and IPOL. For
all three antibodies, the RCC curves were indistinguishable, showing no
apparent difference in MMR immunogenicity whether administered with
Kinrix or separate Infanrix and IPOL vaccines.

Reactogenicity data focused on solicited local events, that is, pain,
redness, swelling, and increased arm circumference occurring at the
DTaP-based injection site within four days of vaccination.
Injection-site pain was the most commonly reported local event, reported
by 57 percent of subjects in the Kinrix group and 53 percent in the
coadministered Infanrix and IPOL group. This difference was found to be
statistically significant. Grade 3 pain, that is, pain sufficient to
prevent normal daily activities, was reported by 1.6 percent of Kinrix
recipients and 0.6 percent of Infanrix plus IPOL recipients. This was
also a statistically significant difference. No difference was observed
on reporting of pain resulting in a medical contact. For all other
solicited local events, no clinically or statistically significant
differences between groups were observed.

Limb swelling has been observed in association with the whole cell and
acellular pertussis vaccines. Two categories of swelling events were
defined: large injection-site swelling and increased circumferential
swelling. Large injection-site swelling was defined as greater than 50
millimeters, or an increase in arm circumference greater than 30
millimeters relative to pre-vaccination measurement, or a diffuse
swelling, not measurable, but interfering with normal daily activities.
If a large swelling reaction was noted, the parent was instructed to
notify the study site and to bring the child in for further assessment.
The incidence of large swelling was relatively low and similar between
the treatment groups: 8.4 percent in the Kinrix group and 9.5 percent in
the Infanrix and IPOL group. In the majority of cases, intensity was
considered mild to moderate, and most events resolved within 48 hours.

Increased circumferential swelling, or ICS, was defined as a measure of
clinically significant or severe swelling and as the basis of a
non-inferiority comparison between the vaccines. The study defined it as
a swelling that involved more than 50 percent of the upper arm length
and that had a greater than 30 millimeter increase in upper arm
circumference relative to the baseline measurement. The incidence of ICS
was determined in both groups and the treatment difference between the
groups was determined with a 95 percent confidence interval.
Non-inferiority was defined as the upper limit of the 95 percent
confidence interval for the group difference being less than or equal to
two. In the Kinrix group, 0.6 percent of the recipients displayed
increased circumferential swelling, whereas one percent of those in the
Infanrix plus IPOL group had swelling meeting the criteria for ICS. This
gives a treatment difference of minus 0.41 percent with the upper level
of the 95 percent confidence interval on the difference being 0.16. This
is less than 2 percent, which enables a conclusion of non-inferiority of
Kinrix to Infanrix and IPOL with respect to association with increased
circumferential swelling.

Regarding the incidence of solicited general symptoms within four days
of vaccination, i.e., drowsiness, fever, and loss of appetite of any or
Grade 3 intensity, no clinically or statistically significant
differences between the treatment groups were noted. Unsolicited adverse
events and SAEs were reported by comparable proportions of subjects in
both groups. There were no fatalities reported during the study, no
clinically relevant differences between groups, and the reporting of
unsolicited AEs was noted. No SAEs reported were considered to be
causally related to vaccination.

In conclusion, the data show that immune responses and reactogenicity
were comparable between the groups receiving Kinrix vaccine and
receiving Infanrix co-administered with IPOL. No differential effect on
immunogenicity of a co-administered MMR vaccine was noted between Kinrix
and Infanrix plus IPOL groups. Kinrix is expected to provide protection
comparable to Infanrix and IPOL, with one fewer injection required.

**Discussion**

Dr. Englund asked whether the studies had looked for pre-existing
diphtheria or the impact of diphtheria antibody to explain the large
amount of entire limb swelling seen. Dr. Weston replied that no
comparison was made on the basis of prior diphtheria or tetanus
antibodies. The study did look at subjects who had a large swelling
reaction or a whole-limb swelling reaction to a prior dose of
DTaP-containing vaccine, and found no association between prior reaction
to a DTaP vaccine and current incidence of a larger increased
circumferential swelling. The incidence of large swelling was comparable
to what has been seen in previous literature.

Dr. Neuzil said she assumed that Kinrix was given in one arm, and
Infanrix in the same arm and polio in the other arm, so the comparison
where more pain was seen with the Kinrix was just based on the arm that
DTaP was given in. Dr. Weston confirmed that this was so.

Dr. Katz asked whether any studies had been done of Kinrix as primary
immunization for vaccine-naive children who might just get the DTaP and
IPV as their primaries. Dr. Weston answered that no such studies had
been done or were planned.

Dr. Turner asked about the charts showing the number of shots saved and
what the age cut-off was. Dr. Wallace replied that it was through the
four- to six-year-old preschool visit.

Dr. Englund asked whether any children had had a previous large limb
swelling in the past and noted that this might be a safety question. Dr.
Weston said that some children had, but he could not give exact numbers
or percentages. Dr. Wallace added that CDC looked at the incidence of
whole-limb swelling among those who had gotten all Infanrix or all
Tripedia. No difference was found in antibody levels either. He felt the
cause would probably be cell mediated rather than immune globulin
levels.

Dr. Chilton commented that currently the administration fee given to
practitioners is dependent on the number of shots, not the number of
antigens, so many pediatricians must decide whether to spare pain or to
earn more money. Dr. Wallace said that issue had already been identified
and that there had also been discussions about CPT codes and the amount
of education required.

Dr. Morse wondered whether combination vaccines made it easier or more
complicated when patients move around frequently.

Dr. Judson asked if the studies had concluded that the IPV component had
no reactogenicity. Dr. Weston replied that he had not presented those
data because DTaP was generally considered the more reactogenetic
vaccine. The incidence of any pain associated with the DTaP injection
site was similar to the proportion of patients reporting any pain at any
injection site. With Kinrix, there is no separate IPV site. In the
separate Infanrix and IPOL group, about 30 percent of all patients
reported pain at the IPV site. So looking at the 53 percent of subjects
reporting pain at the DTaP injection site, about half that number also
reported pain at the IPV site. Dr. Judson noted that the confidence
intervals largely overlap and that for all other indications of
inflammation or reactogenicity, the GSK combination seemed to be less
reactogenetic. Dr. Weston replied that there did not seem to be
increased reactogenicity for redness, swelling, or increased arm
circumference with the addition of the IPV to the DTaP. A little
additional pain was reported.

**Immunization Schedule for HIV-infected Adults**

**Dr. Gina Mootrey, CDC/NCIRD/ISD**

Dr. Mootrey explained that the concept of an immunization schedule for
HIV-infected adults came out of a request from the CDC-NIH- IDSA working
group to revise the guidelines for prevention and treatment of
opportunistic infections in HIV-infected persons. The working group
started with the adult immunization schedule approved in June by this
committee, and modified it with input from ACIP\'s HPV working group,
CDC subject-matter experts for each of the specific vaccines, and the
opportunistic infections guidelines workgroup.

Yellow bars mean the indication is for all persons in the category who
meet the age requirements and who lack evidence of immunity; the purple
bars indicate the recommendation if some other risk factor is present.
The title was changed from "Recommended Immunization Schedule" to
"Immunization Schedule." The order of the vaccines was changed in order
to put those that have an actual indication for use first, i.e.,
influenza, pneumococcal, and hepatitis B. The zoster vaccine is not on
this schedule.

Regarding influenza vaccine, the indication is only for the trivalent
inactivated vaccine, and the bar is yellow for all of the age groups.
For pneumococcal polysaccharide vaccine and hepatitis B, it is also
yellow for all age groups for this schedule. There are no changes for
the tetanus, diphtheria, pertussis vaccine. For the HPV vaccine, the
number of doses was removed and it just says three doses for females,
which allows some flexibility if there is licensure of an additional
vaccine before there is a new schedule. MMR vaccine and varicella
vaccines are yellow for all ages, and include the words, "Do not
administer to severely immunosuppressed persons." This is consistent
with the childhood schedule indications. For hepatitis A vaccine and
meningococcal vaccine there were no changes. The box that describes the
schedule now includes a phrase stating that it has been adapted for
HIV-infected persons.

There were a number of footnote modifications. For influenza
vaccination, the list of medical, occupational, and other indications
was removed because there is specific language saying that it is
indicated for HIV-infected individuals and the other indications really
were not necessary. It mentions that LAIV is contraindicated, and
wording about household contacts. The list of medical and other
indications for pneumococcal vaccination was removed for the same
reason. It was reworded to focus on HIV-infected persons, noting that
there could be better efficacy with higher CD4 counts.

Trivalent inactivated vaccine for influenza is specifically mentioned.
LAIV is contraindicated, and vaccination of persons who are household
contacts or caregivers for persons with HIV is recommended. Either TIV
or LAIV may be used for those individuals.

Pneumococcal polysaccharide vaccine is recommended for immunosuppressive
conditions, including HIV. The phrase "Vaccination should take place as
close to the time of diagnosis as possible" will be removed. For
revaccination with pneumococcal vaccine, the language now just says for
persons greater than or equal to 65 years, a one-time revaccination if
they were vaccinated five or more years previously and were less than 65
at the time of primary vaccination. For pneumococcal vaccine, the
footnote says it is recommended for HIV-infected adults and better
efficacy is anticipated for persons with higher CD4 and T-lymphocyte
counts.

The hepatitis B footnote has some additional language. Vaccination is
recommended for all adults with HIV infection. The vaccine series
consists of three doses given at zero, one to two, and four to six
months. The addition is "*Humoral response to hepatitis B vaccination
might be reduced in persons with HIV infection. Modified dosing
regimens, including doubling the standard antigen dose or administering
additional doses, have been found to increase response rates. However,
limited data regarding response to these alternative vaccination
schedules are available."*

There is also new language on post-vaccination testing.
"*Post-vaccination testing is recommended for susceptible HIV-infected
persons. Testing should be performed one to two months after
administration of the last dose of the vaccine series, using a method
that allows determination of a protective concentration of anti-HBS
greater than ten. Persons found to have anti-HBS concentrations of less
than ten after the primary vaccine series should be revaccinated.
Administration of three doses on an appropriate schedule followed by
anti-HBS testing one to two months after the third dose usually is more
practical than serologic testing after one or more doses of vaccine."*

For Tdap there are currently no changes shown on the schedule, but there
has been a suggestion to delete the text related to pregnancy because it
was not sufficiently HIV focused.

In the HPV vaccination footnote, the language has been changed from "Not
specifically recommended for females" with the medical conditions
phrase, to "Not specifically recommended for females with HIV
infection." Language was added that there are no data in HIV-infected
persons. "One of the four" was changed to "one or more of the
HPV-vaccine types" and a phrase was added for the quadrivalent vaccine.

The footnote now reads, "*Although HPV vaccination is not specifically
recommended for females with HIV infection, it is not a live-virus
vaccine and can be administered. However, the immune response in vaccine
efficacy might be less than that in persons who are immunocompetent.
There are no data in HIV-infected persons at this time."*

Other changes include: *"Vaccination is less beneficial for women who
have already been infected with one or more of the HPV-vaccine types,"*
and then in the last paragraph, "*For the quadrivalent HPV vaccine, a
complete series consists of three doses. A second dose should be
administered two months after the first, and the third dose should be
administered six months after the first."* The only change there is the
addition of the word "quadrivalent."

For the MMR footnote, an indication has been added for HIV-infected
persons who have CD4 T-lymphocyte counts greater than or equal to 200
cells per microliter. In addition, there is an indication to withhold
measles-containing vaccines from HIV-infected persons with severe
immunosuppression and language was added regarding vaccination of close
contacts of HIV-infected persons. So the footnote now says. *"MMR
vaccination is recommended for all asymptomatic HIV-infected persons
with a CD4 T-lymphocyte count greater than or equal to 200 cells per
microliter who do not have evidence of severe immunosuppression and for
whom measles vaccination would otherwise be indicated. MMR vaccination
should also be considered for all symptomatic HIV-infected persons who
do not have evidence of severe immunosuppression. Withhold MMR or other
measles-containing vaccines from HIV-infected persons with severe
immunosuppression. All family and other close contacts of HIV-infected
persons should be vaccinated with MMR vaccine unless they have
acceptable evidence of measles immunity."* This language is from the
ACIP-MMR statement.

For the varicella vaccination footnote, the lengthy discussion of
evidence of immunity was removed, and language was added on vaccination
of HIV-infected adults with CD4 T-lymphocyte counts greater than or
equal to 200 cells per microliter, which were taken from the June
varicella ACIP recommendations. It now reads, "*HIV-infected adults
without evidence of immunity may be considered for varicella vaccination
\-- two doses, three months apart \-- provided they are not severely
immunocompromised. Limited data from HIV-infected children aged one to
eight years indicated that the vaccine was well tolerated and that
greater than 80 percent of subjects had detectable immune response at
one year after immunization.* *Data on the use of varicella vaccine in
HIV-infected adolescents and adults are lacking. However, on the basis
of expert opinion, the safety of varicella vaccine in HIV-infected
persons aged greater than eight years with similar levels of immune
function, meaning CD4 T-lymphocyte count greater than or equal to 200
cells per microliter, is likely to be similar to that of children aged
less than or equal to eight years. Immunogenicity might be lower in
these groups compared to children one to eight years."*

For hepatitis A vaccine, the language now reads as follows: *"If the
combined hepatitis A and hepatitis B vaccine is used, administer three
doses at zero, one, and six months or four doses at 0, 7, 21 to 30 days,
and 12 months."* The suboptimal response with lower CD4 counts is
mentioned. The word 'lower' was used because there was a difference of
opinion about what specific T-lymphocyte count to mention.

For meningococcal vaccine, language was added on the conjugate and
polysaccharide and revaccination, now reading as follows: *"Patients
with HIV infection are likely at increased risk for meningococcal
disease, although not to the extent that they are at risk for invasive
strep pneumonia infection. Persons with HIV infection can elect to
receive the conjugate or polysaccharide. MC4 is licensed for persons
aged 11 to 55 years. Persons aged greater than or equal to 56 years
should receive the polysaccharide. For persons aged 11 to 55 years who
have been previously vaccinated with the polysaccharide, revaccination
with conjugate is not indicated unless vaccination occurred three to
five years previously and the person still remains at increased risk for
meningococcal disease."*

Dr. Kaplan was one of the four co-chairs of the effort to revise the
guidelines for prevention and treatment of opportunistic infections
(OIs) and combine them into one adult document covering 29 different
diseases, under the auspices of the Office of AIDS Research at NIH. The
challenge was to make that document consistent with the footnotes in
this adult vaccination schedule, particularly for hepatitis A, hepatitis
B and pneumococcus. He mentioned three options for solving this problem.
One would be to have all the OI working groups weigh in on the
footnotes, which would obviously be a huge effort. A second possibility
would be to use the adult immunization figure, which everyone likes, but
drop the footnotes, with one generic footnote referring readers to the
OI guidelines. For those diseases not in the OI guidelines, readers
would be referred to existing ACIP recommendations. This second option
would simplify things greatly, allow the figure to be used with
appropriate credit, and avoid the arduous task of trying to reconcile
the guidelines with these footnotes. The third option would be to drop
the figure, but no one wants to do that.

Dr. Mootrey mentioned that the anticipated submission date for
publication to *MMWR* for the opportunistic infections guidelines was
December 15th.

**Discussion**

Dr. Judson said was disturbed by cognitive dissonance among CDC experts
or divisions making recommendations around the same goal, such as
preventing and controlling HIV, but far more important was the issue of
simply vaccinating people with HIV who are at risk of further
transmission, without connecting the ethical obligation to cease
transmission or cease exposure of others to their HIV infection. These
are critical issues from a broader public health standpoint.

Dr. Craig thought the hepatitis B footnote about doubling the dose or
increasing the number of vaccine doses would be confusing to clinicians.
Dr. Kaplan pointed out that this was an example of where the language in
the guidelines goes into much more detail. The current recommendation is
to use the double dose, and there are good data to support that,
particularly with people with CD4 counts higher than 350.

Dr. Baker asked what the reasoning was behind the suggestion that
pregnant HIV women to drop TD when non-pregnant people get TD every ten
years. She felt it would be ethically wrong to pick out one group that
would not get the benefit of prevention. Dr. Kaplan said referring
people to the OI guidelines would solve that issue.

Dr. Neuzil wondered why zoster vaccine was removed from the schedule.
Dr. Mootrey explained that there had been tremendous push-back at the OI
meeting, immediately before the June ACIP meeting, and there is a
contraindication for the use of zoster vaccine for those with CD4 counts
less than 200. Dr. Neuzil's concern was that there is an increasing
number of HIV-infected adults who are 60 years and over. If there is a
contraindication and no recommendation, it needs to be stated on the
schedule. Dr. Kaplan noted that there was a statement in the OI
guidelines that there is no information on the use of the zoster vaccine
in HIV-infected persons, therefore there is a recommendation against
using it.

Dr. Schuchat recalled that at the October 2006 meeting there was lengthy
discussion about what to do with zoster in HIV-infected persons, whether
there should be a permissive off-label recommendation or whether it
would be better to wait for on-going studies that might reveal any
benefit or any risk to HIV-infected persons. That discussion did not
focus on the 60-and-over population, but for the vast majority of the
population the risks and benefits are unknown. Dr. Benson noted that
Merck was finalizing the details of a protocol for an ACTG study and
awaiting final sign-up from NIH.

Ms. Stinchfield referred to the contraindication for influenza LAIV and
wondered whether a person who was immunocompetent and had a normal CD4
count in an undetectable viral load would be considered a healthy
individual. She suggested using the word "precaution" rather than a
contraindication.

Dr. Neuzil asked whether the table would be just used in the OI
document, or would it also stand independently with the footnotes for
other reasons. Dr. Mootrey responded that the intent was that it just be
part of that document. Dr. Lett felt that if the table were to stand
alone, it would need to have the footnotes. Dr. Schuchat commented that
from her perspective, the OI document would be the Bible for
practitioners who treat HIV patients, rather than ACIP stand-alone
immunization recommendations. So the table would best belong in the
document with adequate supporting information.

Dr. England said that the statement for MMR and varicella, "Do not give
to severe immunocompromised patients" appears to be saying not to give
it. She suggested putting that in parentheses so make it less confusing.

Dr. Judson felt that the overwhelming priorities in HIV care were
suppression of the virus, restoration of immunity, and prevention of
further transmission. Those who actually have HIV will have their care
carefully tailored, by people who weigh information from many experts as
to whether any individual vaccine is indicated. There may be other small
complicated subpopulation groups for whom the ACIP general
recommendations will not be particularly helpful.

Dr. Craig found it strange to vote on this schedule without looking at
all the other material. Dr. Kaplan explained that the OI document was
huge, with 29 different opportunistic disease areas, and tables on
prevention and treatment. The information on immunizations is under each
disease-specific section. The advantage of the figure is that people
like it and it also incorporates standard adult recommendations. Dr.
Seward added that the ACIP approved the pediatric schedule with
footnotes in June, using the same process as the adult schedule, i.e.,
language was abstracted from approved ACIP statements, with no new
recommendations, and this had just been pulled into one document for
HIV. The variations presented were from comments received following that
first iteration.

Dr. Hull was inclined to turn the table over to the OI group. ACIP has
made its recommendations and perhaps a new document is not needed. The
committees does not have the expertise to delve into the fine points of
caring for AIDS patients. Dr. Morse suggested calling the table an
adaptation of existing ACIP statements and not vote on it.

Dr. Schuchat felt it was unfair to ask the ACIP to vote on text they
have not been able to review. It defeats the purpose of having a
deliberative process. Dr. Pickering thought it was still important to
harmonize ACIP recommendations with those in the OI document. Dr. Baker
noted that there seemed to be full compatibility on HIV pediatric
patients. Dr. Morse concluded that since there seemed to be no consensus
about voting, the alternative would be for the OI group to cite ACIP in
their document. Dr. Mootrey could work with them to make sure there is
harmonization. Mr. Beck said he was still uncomfortable with
harmonization, because of the current difficulty coming to agreement on
language. He felt the committee should at least be able to review
content of another document.

Dr. Hull was curious about whether there was a requirement that ACIP
pass on the recommendations and immunization made by another group. Dr.
Pickering said the charter stipulates making recommendations for the
civilian population, when asked. Dr. Morse said the usual procedure
would be to send it back to the adult immunization committee to review
the language and bring a consensus recommendation back in February,
which would slow up publication.

Mr. Beck asked who had responsibility for the accuracy of the OI
document. Dr. Kaplan said it had to be approved by all the participating
agencies, including all the appropriate divisions at CDC, not to mention
the expertise of about a hundred panel members. In-depth review and
clearance will incorporate the thoughts of ACIP.

Mr. Beck moved that the document be returned to the organization from
which it came, with the direction that they harmonize the contents with
ACIP recommendations.

Dr. Craig seconded the motion. Dr. Schuchat stated that this did not
need an official vote, so Mr. Beck withdrew his motion and Dr. Craig
withdrew his second. The consensus was not to vote on this issue.

**Vaccine Supply**

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

Dr. Wallace started with hepatitis A vaccine and reminded the audience
that Merck had reported some supply issues in July, with backorders in
both their pediatric and adult preparation. Since GSK indicated at that
time that they had adequate supplies, no changes were recommended in the
ACIP schedule by the recurring *ad-hoc* supply group. Currently
backorders are suspended for the adult and pediatric vial formulations,
and possibly for the adult syringes as well, although there may be some
of that preparation still left. Current projections are for a return to
the market late in the first quarter of 2008, dependent upon remediation
actions and approval with FDA. There continues to be adequate supply
from GSK, and no change in the ACIP recommendation.

Regarding the varicella-based vaccine supply, varicella-zoster virus
bulk is used to manufacture varicella vaccine (Varivax), MMRV vaccine
(ProQuad) and the zoster vaccine (Zostavax). Merck experienced lower
than expected yields in their process and temporarily suspended the
production of their bulk product. However, they have adequate bulk to
make the varicella vaccine, which takes less titer than the ProQuad, and
also the zoster vaccine, which has a lower demand than the routine
pediatric vaccines. Again, no changes were made to the current vaccine
policy recommendations, but people were informed that ProQuad was
temporarily unavailable. A notice went out in February of 2007,
announcing that Merck was prioritizing the production of varicella
vaccine and zoster vaccine, and expected MMRV to run out by the end of
the year. This resulted in a big run on vaccine and ProQuad ran out even
sooner. ProQuad orders were suspended in June. Merck still has adequate
bulk supply to make Varivax and Zostavax. Also, with the new two-dose
pre-school recommendation, the run on vaccine lasted longer and doses
ordered increased faster than projected. Shipping delays are starting to
decrease back to the four- to five-week level and should settle down
over the winter. The committee and the public will be informed as
updates on remediation are received.

Dr. Wallace presented some graphs showing the history of influenza
vaccine production and distribution. Influenza vaccination was not a big
program going through the eighties, but then there was a large increase
in production and distribution during the nineties. In the past 7-10
years, there were fluctuations and some flattening out, with delays in
2000-2002. But in 2003, production and distribution were nearly
equivalent, which was followed by media reports of pediatric deaths and
another outcry about not having enough vaccine. In 2004, there was a
vaccine shortage due to a manufacturing failure, followed by an
unprecedented increase in vaccine production. Demand is also growing,
but not at the same rate as production.

Ninety-five million doses had been distributed through the third week in
October 2007. Finishing distribution by October is considered the gold
standard. These data represent distribution from the manufacturer, so
there is another layer of distribution from the major distributors. The
goal is to get out over a 100 million doses in a couple of months time,
so timing becomes very critical. With the different age recommendations
for different vaccine preparations, implementation can be very
complicated.

A major challenge is how to project pediatric vaccine in a changing
world. Dr. Wallace presented a graph showing distribution of hepatitis B
pediatric vaccine, Tdap, Hib, MMR, hepatitis A, varicella and rotavirus
to demonstrate his point that one cannot empirically predict market
demand.

Regarding implementation of new adolescent recommendations, Menactra had
some limitations the first year and the public sector did not purchase
much vaccine the second year. Anecdotally, there was some vaccine left
over from the previous year.

Now that the recommendations have been generalized, 2007 is already
showing good uptake, in the public sector as well, and it appears to
reflect real administration. There has been a flattening of Tdap in the
public sector, but sanofi pasteur reported an increase in demand, based
on claims data for adults. It is harder to evaluate adolescents and
adults when some of the recommendations cross age groups.

For HPV, there initially were concerns about price and being able to
stock it, so the public sector portion in 2006 was probably larger than
normal for adolescent vaccines. While there has been an increase in the
amount of HPV in the public sector in 2007, it is a smaller proportion
than before. Some of this is due to the private sector catching up and
some adult vaccination may be going on as well.

There are some caveats regarding the adolescent doses. Much of the 2007
demand occurred during the third quarter when adolescents were going
back to school. Whether that trend sustains over time remains to be
seen. The system is also undergoing a step-by-step transition to a
federal or nationalized third-party distribution for the public sector,
which requires some seeding of inventory. However, it is very difficult
to evaluate trends, especially when doses are going to both adults and
adolescents with changing recommendations. Regarding combination
vaccines, manufacturers say that trying to predict seasonal demand,
which can be led by funding and other issues, makes it hard to plan
production.

**Discussion**

Dr. Lett asked whether the six- to seven-week delay in varicella, which
had forced providers in her state to prioritize and sometimes only give
a first dose, was occurring elsewhere and whether the ACIP would be
providing any guidance about prioritization. Dr. Wallace said he had not
been getting complaints. There had been some unpredicted demand, but the
situation seemed to be easing.

**Public Comment**

Ms. Diane McGowan spoke on behalf of her son Martin, who died from the
flu at age 15. He was healthy and active, but not vaccinated and not
part of any recommendation. She felt the committee was on track to vote
for a universal vaccination, but without a vote, families are facing
another potentially deadly flu season. She read the names of a few of
the numerous children who died of flu during the recent flu season, none
of whom were in the current recommendation, and urged the committee to
vote for a universal vaccination in February.

Mr. Gary Stein, whose family lost a daughter to influenza when she was
four and half, said that board members of Family Fighting Flu were
dedicated to advocating to parents the importance of flu vaccination and
to spreading awareness of the importance of this disease. ACIP's
ultimate recommendation to move to a universal pediatric recommendation
will help immensely. He expressed appreciation for the progress and
discussion so far, but urged the committee to vote as soon as possible
to expand the recommendation.

Dr. Plotkin spoke about a new national lay organization being formed
that would speak in favor in vaccination and counter the impact of
anti-vaccination organizations on immunization coverage. Seed money was
found and the Task Force for Child Survival was engaged to get this
organization off the ground. Alan Hinman, formerly with CDC, is putting
together documents and applications to foundations. It is believed that
the organization should be led by lay people and not accept funds from
manufacturers or from the government, so contributions and support from
all who believe in immunization would be greatly appreciated. The Task
Force for Child Survival is a 501(c)(3) organization, so contributions
are tax deductible.

**October 25, 2007 - Day Two**

Dr. Morse welcomed Ciro Sumaya and asked whether he had any conflicts to
declare. Dr. Sumaya said he had no conflicts.

**[Human Papillomavirus (HPV) Vaccines]{.mark}**

**[Dr. Janet Englund, ACIP, WG Chair]{.mark}**

**[Dr. Lauri Markowitz, CDC/NCHHSTP/DSTDP]{.mark}**

**[Dr. Richard Haupt, Merck]{.mark}**

**[Dr. Martine Wettendorff, GSK]{.mark}**

**[Dr. Gary Dubin, GSK]{.mark}**

**[Dr. Elizabeth Unger, CDC/NCZVED]{.mark}**

**[Dr. Eileen Dunne, CDC/HCHHSTP/DSTDP]{.mark}**

[]{.mark}

**[Introduction]{.mark}**

[]{.mark}

[Dr. Englund introduced potential issues for the February ACIP meeting,
including recommendations for a bivalent HPV vaccine and issues related
to having two licensed HPV vaccines. The BLA for the bivalent vaccine
was submitted to the FDA in March of 2007 and a decision is anticipated
in January 2008. The HPV vaccine working group has also been discussing
bivalent HPV vaccine efficacy, immunogenicity, and safety; quadrivalent
HPV vaccine cross-protection; VAERS data and vaccine safety; recurrent
respiratory papillomatosis and genital warts; cost effectiveness of both
the bivalent and quadrivalent vaccines; vaccination of HPV-infected
adults; and HPV in older women.]{.mark}

[]{.mark}

**[Overview of HPV Vaccine Trial Data]{.mark}**

[]{.mark}

[Dr. Markowitz noted that a substantial amount of data had been
published and presented in the last six months. Her presentation
provided background on efficacy and immunogenicity, safety issues and
ongoing and planned trials by both manufacturers.]{.mark}

[There are over 100 different HPV types, which differ by end disease
association. About 40 types are mucosal and sexually transmitted; these
are classified as high or low risk based on their association with
cervical cancer. The high-risk, or the oncogenic, types include 16 and
18, which cause about 70 percent of cervical cancers worldwide. Low-risk
types include 6 and 11, causing over 90 percent of genital warts and
almost all recurrent respiratory papilomatosis or]{.mark} RRP. [HPV also
causes other anogenital cancers.]{.mark}

[There are two L1 virus-like particle, or VLP, vaccines. The HPV L1
capsid protein is the antigen used for immunization, and expression of
the L1 protein is done using recombinant technology. The L1 proteins
self-assemble into virus-like particles which are noninfectious and
contain no viral DNA.]{.mark}

[The quadrivalent vaccine developed by Merck includes two low-risk type
VLPs \-- 6 and 11 \-- and two high-risk type VLPs\-- 16 and 18, while
the GSK bivalent vaccine includes two high risk typeVLPs \-- 16 and 18.
The quadrivalent vaccine is produced in a yeast substrate and the
bivalent vaccine is produced in the Baculovirus system in insect cells.
Both are given intramuscularly in a three-dose schedule, but the timing
of the second dose differs slightly. The quadrivalent vaccine uses an
adjuvant containing aluminum hydroxyphosphate sulfate, used in other
vaccines, and the bivalent contains a new adjuvant, AS04, containing
alum and monophosphoryl lipid A. This adjuvant is not in any vaccine in
widespread use around the world or licensed for use in the U.S. The
quadrivalent vaccine was licensed by the FDA in June 2006 and is now
licensed in over 80 different countries worldwide. The bivalent vaccine
was submitted for licensure in March of 2007, and has been recently
licensed in the European Union, Australia and Mexico, and several other
countries.]{.mark}

[Both vaccines have had large clinical development programs. After the
preclinical and the Phase I trials, Phase II efficacy trials were
conducted in females either 16 to 23 or 15 to 25 years of age, and these
trials were powered primarily to detect virologic endpoints. Large
pivotal efficacy trials were conducted in similar-aged women, powered to
detect histologic endpoints such as cervical intraepithelial
neoplasia.]{.mark}

[Adolescent immunogenicity and safety studies were conducted to bridge
the antibody results from the efficacy trials in the older females. On
the basis of these studies, the vaccines have received indications for
use down to nine or ten years of age. Smaller efficacy and
immunogenicity studies have been or are being done also in older women
by both companies. Merck is also conducting efficacy trials in
men.]{.mark}

[For the quadrivalent vaccine, there were two Phase II trials and two
Phase III trials, called Future I and Future II, with slightly different
protocols. Both were large, multinational, multisite trials. Phase III
trials enrolled women from North America, Latin America, Europe, and
Asia. Over 21,000 women were included in these combined Phase II and
Phase III trials. Similarly large trials were conducted for the bivalent
vaccine. There was a Phase II trial conducted in North America and Latin
America, and one large efficacy Phase III trial, also a multinational,
multisite trial. There over 19,000 women in these two combined trials.
Another ongoing efficacy trial of the bivalent vaccine is being
conducted in Costa Rica by the National Cancer Institute.]{.mark}

[Regarding efficacy, these trials had similar endpoints, such as
persistent infection or cervical intraepithelial neoplasia (CIN), grade
2 or 3, but they used slightly different protocols for detecting HPV and
for screening and management of the abnormal cytology results. A variety
of different efficacy analysis populations were used. Most women were
sexually active and enrolled without regard to their HPV-PCR antibody
status. The main analyses have or will be done in the per-protocol
population, which includes women without evidence of infection with the
relevant vaccine type through one month after the third dose, which is
Month 7; they received all three vaccinations, did not deviate from the
protocol, and cases were counted after dose 3. Some of the trials also
analyzed the unrestricted-susceptible population or the total vaccinated
population. These women were naïve to the relevant HPV type at baseline,
had received at least one vaccination, and cases were counted after the
first dose. The intent-to-treat population, which included all subjects
regardless of their baseline status, received at least one vaccination,
and cases were counted after dose 1.]{.mark}

[The major endpoint was CIN 2/3 or adenocarcinoma in situ (AIS) from the
quadrivalent and the bivalent vaccine trials. The main analysis for the
quadrivalent vaccine was done in the per-protocol population, where
vaccine efficacy was 98 percent with one case in over 5,000 women. For
the Future II study, results for the unrestricted population, women who
received at least one dose, showed 95 percent efficacy. For the bivalent
trial and unrestricted analysis, efficacy was 90 percent with only two
cases in the vaccine group.]{.mark}

[For both the quadrivalent and the bivalent vaccine trials, cases in the
vaccine groups had a non-oncogenic type that was detected in a preceding
specimen as well as in the CIN 2/3 lesion. When analyses were done using
lesions believed to be causally associated with the vaccine type, the
analyses showed even higher efficacy, with both vaccines having efficacy
of 100 percent. GSK has published results showing 100 percent efficacy
with this modified, revised analysis.]{.mark}

[High efficacy was found for both HPV vaccines for prevention of CIN 2/3
or AIS due to HPV 16 and 18 separately. There were small numbers of
cases due to HPV 18 in the bivalent vaccine trial. The quadrivalent
vaccine trials have also evaluated other endpoints, some due to HPV 6
and 11. In the per-protocol populations, there was 100 percent efficacy
for prevention of genital warts or condyloma, and vulvar or vaginal
cancer precursor lesions, VIN or VaIN 2/3.]{.mark}

[For the quadrivalent vaccine, in women who were HPV-PCR positive with
or without antibody, there was no evidence of therapeutic efficacy to
the respective vaccine types. Among women who were antibody positive and
PCR negative, suggesting a cleared infection, there was a high point
estimate of efficacy, but there were few cases in that group. In the
PCR-positive group, there was no efficacy. Data published on subjects
enrolled in the ongoing trial in Costa Rica show the bivalent vaccine
had no impact on viral clearance among those infected at
enrollment.]{.mark}

[Overall efficacy for the quadrivalent vaccine has been published,
including all women regardless of their infection status at baseline --
the intent-to-treat population. About 27 percent had evidence of prior
exposure or ongoing exposure with one or more of the four vaccine types,
therefore the efficacy in this total population was lower than in the
HPV-naïve women. Looking at the combined data for three of the
quadrivalent HPV vaccine trials, efficacy for CIN 2/3 was 41 percent;
for VIN or VaIN, 71 percent; and for vulvar or vaginal lesions,
including genital warts, 78 percent. Although efficacy was lower in this
intent-to-treat population, it increased with time since vaccination,
because most of the disease outcomes in both the vaccine and the placebo
group were due to infections present at the time of enrollment.]{.mark}

[Regarding duration of protection, the mean follow-up time published or
presented is three years for the quadrivalent vaccine and 15 months for
the bivalent vaccine. However, from the smaller Phase II trials for both
vaccines, follow-up data through about five years demonstate excellent
duration of protection. For the quadrivalent vaccine, various endpoints
have been high through five years, including for persistent infection,
CIN 1-3, and condyloma. For the bivalent vaccine, with follow-up through
five and a half years, there is high efficacy for various endpoints,
including incident infection, 12-month persistent infection, and CIN
lesions.]{.mark}

[The issue around cross-protection is whether the vaccines provide
protection against related HPV types that are not in the vaccines, which
would increase the impact of the vaccines on cervical cancer. While 70
percent of cervical cancers are due to HPV 16, other oncogenic types are
responsible for an additional small percentages. On the phylogenetic
tree for HPV, the focus has been on two groups: the A9 species, which
contains HPV 16 and related types, and the A7 species, which contains
HPV 18 and related types. The published Phase III trial for the bivalent
vaccine looked at cross-protection using six-month persistent infection
as the endpoint, and observed cross-protection for some other types,
e.g., type 45 (related to 18) and types 31 and 52 (related to type 16).
Significant protection was found against a combination of all tested 12
non-vaccine types using a 12-month persistent endpoint; efficacy was 27
percent.]{.mark}

[The analysis of cross-protection for the quadrivalent vaccine grouped
types by their phylogenetic relationships. There was significant
protection against nonvaccine types in the A9 species and a 47 percent
point estimate efficacy for the seven A7 species.]{.mark}

[In terms of the immunogenicity data, the main basis of protection is
neutralizing antibody. The minimum protective antibody threshold is not
known, due to the high efficacy seen to date in the vaccine trials.
Serologic tests for HPV have not been standardized. Merck has been using
a competitive Luminex immunoassay, which measures antibody to
neutralizing epitopes on the L1 VLP. GSK is using a type-specific ELISA.
Difference in the methods of antibody detection preclude direct
comparison of the type-specific antibody titers within studies and
between the two vaccines.]{.mark}

[Both vaccines have been found to be very immunogenic. For the
quadrivalent vaccine, 100 percent of participants had detectable
antibody to all four types one month after the first dose, and by month
36 seropositivity was still high for all types. HPV 18 had fallen to 84
percent, but there were no breakthrough infections associated with the
lack of detection of antibody. Both vaccines have been found to produce
antibody titers substantially higher than those after natural infection.
For the quadrivalent vaccine, the vaccine-induced antibody is
substantially higher than after natural infection, falling and then
plateauing at about 18 months and remaining fairly stable through 60
months. Administration of a challenge dose at month 60 resulted in a
potent anamnestic response and a rapid increase in antibody titers,
suggesting immune memory.]{.mark}

[Bridging immunogenicity studies conducted by both manufacturers found
that immunogenicity in adolescents was non-inferior to the older women
in the Phase III trials. Seropositivity rates were similar, over 99
percent, and GMTs were twofold higher in the younger age group compared
to the older women. Data from the immunogenicity study in older women
(26 to 55 years) for the bivalent vaccine showed 100 percent
seropositivity after three doses; there were age-related differences in
peak GMTs, but they were all still very high. The quadrivalent vaccine
studies are ongoing.]{.mark}

[Multiple safety outcomes have been evaluated, including injection-site
reactions; serious adverse events; new onset chronic diseases, including
new onset autoimmune diseases; and pregnancy and pregnancy-related
outcomes. Injection-site events occurred more commonly in the vaccine
than in control subjects for both vaccines. There was no significant
increase in serious adverse events or new onset chronic diseases, and no
differences in overall pregnancy outcomes between the vaccine or control
groups.]{.mark}

[A large amount of data will be coming in from ongoing trials being
conducted by both companies. First, there will be follow-up of the Phase
II and Phase III trials, including females who were vaccinated in
adolescence in the immunogenicity trials. There will be immunogenicity
and efficacy data in females greater than 25 years of age and data from
efficacy trials in men 16 to 26 years of age for the quadrivalent
vaccine. On-going studies are looking at simultaneous administration of
HPV with other routinely administered vaccines, and those data will be
available from both companies. GSK is conducting a comparative
immunogenicity study of the two vaccines, a head-to-head trial enrolling
about 1000 women. Both companies are looking at safety and
immunogenicity in HIV-infected women and, in the case of the
quadrivalent vaccine, also in HIV-infected men. Finally, both companies
have large Phase IV trials looking at long-term follow-up.]{.mark}

[]{.mark}

**[Quadrivalent HPV Vaccine Cross-Protection]{.mark}**

[]{.mark}

[Dr. Haupt discussed the impact of the cross-protection efficacy of
Gardasil in the context of co-infection with vaccine and novaccine HPV
types. Even after accounting for co-infection, administration of
Gardasil to HPV-naive women resulted in a clinically important reduction
in CIN 2/3 and AIS due to cross-protection.]{.mark}

[The alpha genus of the HPV phylogenetic tree is where most of the HPV
strains that cause genital infection reside. Since the alpha genus HPV
types are defined by their amino acid sequence to the L1 protein, they
all share at least 65 percent amino acid sequence homology to the L1
protein. Within the alpha genus, there is the A9 species, whose
prototype is type 16, and there is A7, characterized by type 18. To be
within a similar species, the amino acid sequence homology has to be at
least 75 percent shared. Type 16 alone contributes to 55-60 percent and
type 18 contributes another 10 to 15 percent; the A9 species contributes
70 percent and A7 contributes another 20 percent. So these two species
account for about 90 percent of all cervical cancers. Three other minor
species contribute to the rest.]{.mark}

[In clinical trials, Merck tested for 14 different HPV types -- Types 6,
11, 16, and 18 and ten additional oncogenic strains, mostly A9 or A7
family members. This was the baseline data. Women were randomized to the
vaccine or placebo. About a third of the women in the clinical-trial
database were already infected with at least one HPV type at baseline
and of those, about half were infected with more than one type. Type 16
is the most prevalent type in the clinical database in terms of
baseline-infection rate, but many types are found at baseline. HPV
infection is common and sexually active women are at risk for getting
infected from all types.]{.mark}

[Another analysis tried to attribute different HPV types to cervical
disease seen in the placebo arm of the clinical trials, using women who
were negative to all 14 types by PCR testing at baseline and
serologically negative at baseline to the four types in the vaccine. In
addition, women were required to have a normal Pap test: this served as
a proxy for evidence of not being infected with other genital HPV types
not tested for at baseline. The study then was able to look at new
cervical-disease lesions, incident CIN 1/2/3, caused by incident
infections with the genital HPV types. Over 80 percent of the incident
cases of CIN 2 and CIN 3 in the clinical trials were caused by either
HPV 16 or one of its related members. The data also indicated that when
going from CIN 1 to CIN 3, there is an increase in the relative
contribution of HPV 16 to the higher grade lesions.]{.mark}

[The baseline data led to the conclusion that the contribution of HPV
types varies depending on the type of lesion, but when looking at
cancer, Types16 and 18 are by far the most important, contributing 70 to
85 percent of all cervical cancers around the world. The next five, all
related to 16/18, contributed another 15 percent. When looking at
high-grade lesions, type 16 is very important, but members related to 18
become less important and there is more co-infection with other types.
In the lowest grade, type 16 is still the most important, but many other
types also contribute.]{.mark}

[When designing the cross-protection evaluation, the first task was to
decide which types to look at. After types 16/18, types 45, 31, 33, 52,
and 58 each contribute at least 2 percent of the cervical cancer burden
around the world. Each of these also shares at least an 80 percent L1
amino acid sequence homology to 16/18, so there is biological
plausibility that neutralizing antibody generated against 16 and 18 from
the vaccine may cross-react and neutralize these other related types. In
fact, there was such evidence through cross-neutralization antibody
studies already done.]{.mark}

[The next decision was which endpoint to use. In the primary vaccine
efficacy deliberations with regulatory agencies, it was determined that
high-grade cervical precancers \-- CIN 2/3 and adenocarcinoma in situ
\-- should be the appropriate endpoints for defining efficacy against
16/18 related cervical cancer in the trials. No opinions from similar
regulatory authorities have been rendered about the correct endpoints to
use for a cross-protection analysis.]{.mark}

[The WHO expert committee on biologic standardizations has suggested
that disease endpoints would be much more rigorous in an efficacy
evaluation for cross-protection. Many infections resolve spontaneously
without intervention, so infections that lead to disease are the most
important for demonstrating efficacy. Recognizing that the nonvaccine
types are less prevalent or less often lead to high-grade cervical
precancer, WHO suggested that a rigorous viral persistence endpoint
could be an alternative endpoint for efficacy analysis, e.g., prevention
of viral persistence at 12 months.]{.mark}

[Merck did two analyses in its Phase III studies. The first looked at a
composite endpoint of prevention of 31, 33, 45, 52, and 58 viral
persistence and demonstrated cross-protection efficacy against that
composite endpoint. While un-blinding the clinical studies data,
researchers recognized that a lot of CIN 2/3 in the trials could not be
attributed to the vaccine types, so there was a pre-specified data
analysis plan to look at the potential impact of the vaccine against
non-vaccine types related to the vaccine types. A cluster endpoint of
31- and 45-related disease was used, along with a cluster endpoint of
the five next most important types after 16 and 18 \-- 31, 33, 45, 52,
and 58. The entire database of the Phase III trials was used to look at
disease endpoints for up to four years.]{.mark}

[Based on analyses of many different populations, including per-protocol
analyses, and different forms of modified intention-to-treat analyses,
it was decided that the best population in which to determine
cross-protection efficacy was the generally HPV-naïve population, i.e.,
women with normal Paps and negative to the 14 types tested. From a
methodological perspective, there was a lot of co-infection and mixed
infection in the clinical trials. If women are generally HPV naïve, it
is more possible to ascribe cross-protection against new infections and
lesions. From a clinical-prevalence perspective, this population more
closely approximates the primary age group recommended to be vaccinated,
the 11- to 12-year-olds.]{.mark}

[There are several sets of results, starting with high-grade disease
lesions and efficacy against CIN 2/3 and adenocarcinoma in situ caused
by types not in the vaccine. For the 31 and 45 endpoint, eight cases
were seen in the Gardasil group, 21 cases of CIN 2/3 and AIS in the
placebo group, with an efficacy of 62 percent, which was statistically
significant. For the other cluster endpoint, \-- 31, 33, 45, 52, and 58
-- there were 27 cases in Gardasil and 48 in the placebo, which is 43
percent efficacy, also statistically significant. Another cluster
endpoint looked at the ten other oncogenic strains outside of the
vaccine types. There were 38 cases in the Gardasil group and 62 in the
placebo group, for a vaccine efficacy of 38 percent, which was
statistically significant. For the A9 species, there were 26 cases in
the Gardasil group and 48 in the placebo group, a point estimate of 45
percent. That too was statistically significant. The point estimate for
the A7 species was similar, but the number of cases was too few to
ascribe statistical significance.]{.mark}

[Results for cross-protecting efficacy for any grade CIN (CIN 2/3 plus
CIN 1) gives a sense of the overall potential reduction in burden of
disease through cross-protection. HPV 16 causes the most cases of
incident CIN of any grade, including CIN 1. A greater mixture of other
HPV types contributes to lower grade lesions, but they do not
necessarily progress to higher grade lesions. Here one begins to see
types 6 and 11, which in addition to causing 90 percent of genital
warts, cause about 10 percent of low-grade cervical pre-cancers or
low-grade cervical dysplasia. In the clinical trials, about 8 percent of
CIN/1 lesions were caused by Types 6 and 11.]{.mark}

[For CIN of any grade and AIS, with the same cluster endpoints, 31 and
45, there were 23 cases in the Gardasil group and 42 in the placebo
group, which is 45 percent efficacy. Using the five-cluster endpoint,
there was 33 percent efficacy. Both of these were statistically
significant. Using the cluster endpoint of the ten oncogenic strains
after 16 and 18, once again, efficacy was at 27 percent, which is
statistically significant. In the stratified analysis, there was
statistically significant efficacy against the A9 species; there was a
similar and positive point estimate in the A7 species, but it did not
achieve statistical significance.]{.mark}

[Dr. Haupt presented three potential clinical scenarios on how
cross-protection may interface with infection from vaccine types. One
would be that the benefit is completely additive. Any disease lesion
caused by the vaccine type is separate and different from the disease
lesion caused by the other types, but that is not a reasonable
assumption based on the data from the clinical trials. The other end of
the spectrum would be to say that every lesion has a vaccine type as
well as one of these others and, therefore, there is no added benefit.
The reasonable choice lies somewhere in the middle. In order to truly
define the clinical benefit for a woman, consider that if a woman has a
CIN 2/3 lesion and HPV 16 and HPV 52 are both found in it, there is
still only one disease lesion and it should not be counted twice in
terms of the efficacy of the vaccine.]{.mark}

[Merck first looked at the efficacy of the vaccine against CIN 2/3
caused by types 16 and 18. There were 51 cases in the placebo group and
none in the vaccine group, for 100 percent efficacy. The vaccine
prevented 51 cases of CIN 2/3. For the group of five types \-- the 31,
33, 45, 52, or 58 related CIN 2/3 \-- there were 48 cases in the placebo
group and 27 cases in the vaccine group, a reduction of another 21
cases, which might seem to be 40 percent additional reduction based upon
cross protection. However out of the total of 99 CIN 2/3 cases, 16 had
co-infection with vaccine types along with the related non-vaccine
types. So if 16 of those CIN 2/3 cases in the placebo group had 16 or 18
and one of the other types, the cross-protection benefit is not 72 cases
-- it is 56. There is, in fact, a net benefit of cross-protection in
terms of serious disease lesions. The analysis showed about 10 percent
additional reduction of CIN 2/3 in this population of women, which is a
real clinical benefit.]{.mark}

[In summary, Merck feels that the clinical benefit of Gardasil has three
major components. The vaccine is almost 100 percent efficacious against
16/18-related disease, and that includes cervical CIN 1/2/3. It also
includes vulvar, VIN 1/2/3, and vaginal VaIN 1/2/3, as well as
adenocarcinoma in situ. Another major component is the 6 and 11
prevention. Again, the efficacy is virtually 100 percent, with
tremendous efficacy against both genital warts and low-grade CIN, caused
by 6 and 11. Lastly, there is an important additional clinical benefit
from cross-protection. In fact, the 38 percent efficacy against ten
oncogenic strains not in the vaccine has a significant clinical impact
for women in terms of reducing disease lesions.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[]{.mark}

[Dr. Neuzil said she understood that part of the reason the study
focused on clusters was power. However, it seemed to her that types 31
and 45 might be driving the efficacy shown and that it may, in fact, be
significantly lower in those other types. Dr. Haupt replied that the
pre-specified analysis to use composite endpoints was indeed based on
power. The contribution of non-vaccine HPV types, especially to
high-grade lesions like CIN 2/3, is lower, but a much larger study would
be required to look at individual type efficacy with statistical power.
Type-specific analyses were done, but those data have limitations based
on the number of cases seen. It is true that 31 and 45 drive this
composite endpoint of the five types because they cause more CIN 2/3
lesions. The efficacy in the trials was driven predominantly off of Type
31. Even though the studies were not designed to look at individual
types with statistical relevancy, positive trends were seen for every
type except 45, where a neutral impact was seen for CIN 2/3. Efficacy
against Type 45 was seen in the persistent-infection analysis. Going
from persistent infection to any CIN to CIN 2/3, the number of cases
became smaller, so it was hard to show efficacy with 45 against
high-grade disease endpoints.]{.mark}

[Dr. Pickering asked if it might be more appropriate to group the
findings according to the phylogenetic tree and show protection within a
species. Dr. Haupt replied that that data were presented according the
prespecified analytic plan, which focused on the five most important
types contributing to cervical cancer after Type 16 and 18. It just
turned out that four were related to 16 as an A9 species, and one of
them was an A7. In the stratified analysis, where types are grouped by
species, most of the efficacy was driven off of efficacy against the A9
species.]{.mark}

[Ms. Stinchfield wondered whether anything could be done to reduce the
vaccine's sting so that it is not a disincentive for Dose 2 and 3. Dr.
Haupt acknowledged complaints and said that from the clinical trial
database, half of the local adverse events could be attributed to the
proprietary aluminum adjuvant used and another half was related to
the]{.mark} viruslike particles[, which do actually hurt. Merck is
educating providers about that side effect and would be willing to
support studies to help reduce pain.]{.mark}

[Dr. Craig asked about the reports of more syncope from this vaccine.
Dr. Haupt replied that syncope was seen equally in the Gardasil and the
placebo group during clinical trials, and it occurred in less than 0.2
percent of all study participants. More syncope has been reported in the
post-licensure time period, but there is no indication that it is
anything other than the idea of getting a needle and a noxious
stimulus.]{.mark}

[Dr. Judson commented that experience over the years with hepatitis B
and other protein-alum combinations indicates that the reactogenic part
is predominantly the alum and that studies that use alum minus the
active protein are not really placebos in terms of reactogenicity. He
asked whether Merck had also looked at tenacity and acid base and other
factors. Dr. Haupt replied that the pH the injection vehicle is neutral
and not all aluminum adjuvants are the same. Merck's is aluminum
hydroxyphosphate sulfate, which acts very differently than aluminum
hydroxide and aluminum phosphate. In fact, it works best in a neutral
pH, the same pH that adsorbs best with the VLPs. Dr. Judson suggested
that the inflammation is partly why it works in terms of recruiting
processing cells.]{.mark}

[Dr. Jeff Duchin asked at what point after immunization these data were
from and whether Merck was planning to continue to monitor the
durability of cross-protection over time as it relates to the 16/18
types and the four components as compared to the cross-protecting
aspects of the vaccine. Dr. Haupt replied that since they were looking
for cross-protection efficacy and it was a modified intention-to-treat
analysis, case counting began after one dose or after Day 1. Merck is
completing the final analysis of the entire Phase III database, so there
will be a four-year follow-up analysis for this group in evaluating
efficacy against 16/18, efficacy against 6 and 11, and also efficacy
against cross-protection. Other post-licensure studies are planned to
evaluate cross-protection in a broader population level as well as
vaccine efficacy at a population level.]{.mark}

[Dr. Cieslak asked for clarification on the number of cases prevented by
vaccine serotypes other than 16 and 18. Dr. Haupt confirmed that there
were five additional cases prevented when there was co-infection with
vaccine type 16/18 or the other five types was factored in, and that
efficacy against 16 and 18 could be inflating the apparent efficacy
against those other types.]{.mark}

[Dr. Hull asked what number a clinician would use when telling a patient
about reduction of the risk of cervical cancer with the vaccine. Dr.
Haupt replied that 78 percent would be a reasonable estimate of the net
incremental benefit of cross-protection, although Merck has avoided
giving a scientific number for overall protective efficacy.]{.mark}

[Dr. Morse asked whether there were any data on GMT elevation for HPV 18
after a booster dose. Dr. Markowitz replied that the same anamnestic
response was seen for all four types in the quadrivalent vaccine. Dr.
Haupt added that their assays were type-specific, neutralizing assays,
using competitive Luminex. Merck was measuring an antibody that competes
with a monoclonal antibody to a known epitope that neutralizes on the
vaccine. It is not a total IgG antibody. In the women that become
nominally seronegative to type 18, no cases of disease have been seen
beyond five years now and they do boost with a challenge dose.]{.mark}

[]{.mark}

**[Bivalent HPV Vaccine ASO4 Adjuvant System]{.mark}**

[]{.mark}

[Dr. Wettendorff explained that GSK's AS04 adjuvant had been
specifically designed to enhance immunogenicity and increase duration of
protection against cervical cancer. The two HPV types responsible for
more than 70 percent of cervical cancer are HPV 16 and 18 and GSK
deliberately chose not to include additional HPV types in its vaccines,
based on concerns about potential interference. Preclinical and clinical
data have shown that when there are more VLPs in the vaccine, the immune
response can be impaired, especially to HPV 18. Impairing the immune
response to HPV 18 could also impact protection against closely related
phylogenetically HPV types, such as HPV 45. Both HPV 18 and 45 are
highly present in adenocarcinoma, are very often detected in very young
women and often escape detection by Pap smear. At sexual debut, young
girls and women will be at risk for infection with oncogenic HPV types
and long-term protection is key. Finally, natural HPV infection does not
always stimulate the immune system; women can be reinfected even if they
are seropositive for HPV types. The GSK vaccine has been designed to
induce high and sustained immune responses of high quality.]{.mark}

[The vaccine contains two components: L1 proteins in the form of VLP
from HPV 16 and 18 (equal amounts of both types) and the proprietary
adjuvant system, AS04. Early dose-range trials showed that, combined
with the AS04 adjuvant system, this combination and this antigen
concentration was giving the peak of antibody response. The AS04
adjuvant is composed of 500 micrograms of aluminum hydroxide and 50
micrograms of monophosphoryl lipid A, or MPL. MPL A is a derivative from
lipopolysaccharide from Salmonella minnesota. Lipopolysaccharides, or
LPS, are a major component of the outer membrane of gram-negative
bacteria. This substance is ubiquitous in nature, with frequent
population exposure. GSK has chemically modified the LPS to assure an
appropriate safety and reactogenicity profile while retaining the
adjuvant property of the molecule.]{.mark}

[AS04 has been designed to enhance immunogenicity and increase duration
of protection. For women over age 25, it is important to consider the
age-related decline of immune response to vaccines. These women are
still at risk of HPV infection. It has been shown that HPV vaccine can
induce antibodies in the serum that can transudate to the genital mucosa
and having higher antibodies in the serum will translate into higher
levels of antibodies at the site of infection.]{.mark}

[Following vaccination, there are two important steps, the first being
the innate response, which is not antigen specific and does not have
memory. The other is the adaptive immune response, which is antigen
specific and includes T and B effector responses as well as memory
responses. The innate immune responses are characterized by the
recruitment of immune cells at the site of infection. Antigen-presenting
cells capture the vaccine antigen and migrate to the lymphoid organs,
where they mature and present the antigen to T cells. Antigen
presentation and T-cell activation within the lymphoid organs is
followed by activation of effector and memory responses that migrate
back through the blood to the tissues. The adaptive immune responses
determine the quantity, quality, and memory of the antigen-specific
immune responses.]{.mark}

[The activation of the antigen-presenting cells at the site of
vaccination is the most important step and this is where MPL has an
effect. On the surface of the antigen-presenting cells are molecules
called \"toll-like receptors,\" which can recognize molecular patterns
from specific pathogens. When the toll-like receptor of an
antigen-presenting cell is activated, it triggers an intracellular
pathway that leads to the production of a specific microenvironment
around the antigen-presenting cells that directs the type of immune
response in the context of the interaction between the T-helper cells
and the antigen-presenting cells.]{.mark}

[Toll-Like Receptor 4 (TLR4) recognizes LPS. Once activated, a cascade
of intracellular events is initiated, leading to the production of
ProTh1cytokines, such IL-12 and interferon gamma, as well chemokine and
proinflammatory cytokines, such as TNF alpha and IL-6. This creates a
specific microenvironment around the antigen-presenting cells, which has
an impact on the induction of the specific antigen responses, the
adaptive immune responses of B and T cells. MPL is actually a derivative
from LPS, and it can act on TLR4 the same way as LPS does.]{.mark}

[When using vaccines containing the antigen and AS04, the MPL triggers
the TLR4 receptor on the antigen-presenting cells, initiating the
cascade of events creating a microenvironment of cytokines around the
antigen-presenting cells. These antigen-presenting cells]{.mark} up the
regulation [of costimulatory molecules, which helps present the vaccine
antigen to specific T cells, resulting in an optimal T- and B-cell
activation.]{.mark}

[Antigen-presenting cells that have cosignals via TLR and the antigens
will optimally activate and differentiate T cells, leading to optimal
adaptive responses. Vaccine containing AS04, via the activation of TLR4,
will have an impact on the quantity, quality, and longevity of the
immune responses against the HPV vaccine antigen. As the MPL effect is
quite local and transient, no adverse immune events relative to
vaccinations with AS04 are expected.]{.mark}

[Dr. Wettendorff then presented data on the impact of MPL and AS04 on
the induction of innate immunity, based on experiments using a monocytic
human cell line that can be activated through TLR4 to produce a
proinflammatory cytokine. In this case, production of TNF alpha was
measured. Stimulation of the cells with MPL induced a dose response to
production of TNF alpha by the cells. When cells were stimulated with
aluminum hydroxide, there was no stimulation of this TLR and no
production of TNF alpha. When MPL was combined with aluminum hydroxide,
the stimulation through TLR4 was maintained, which sets the stage for
optimal adaptive responses later on.]{.mark}

[GSK evaluated the quantity and the persistence of immune responses
induced by the vaccine, the presence of antibodies at the site of
infection in the genital mucosa, and confirmed that this vaccine is able
to induce high antibody titers, whatever the age range. To study the
magnitude of the immune responses in the Phase II clinical trials, two
vaccines were compared that each had 20 micrograms of each L1 VLP from
HPV 16 and 18, but were formulated either with aluminum hydroxide or
with AS04 adjuvant. For HPV 16 and HPV 18, measuring neutralizing
antibody response over a four-year period, there were statistically
significantly higher titers induced by the AS04-containing vaccines as
compared to the aluminum hydroxide vaccine.]{.mark}

[In the same trials, GSK evaluated the impact of the adjuvant on the
induction of memory B cells following the primary vaccination course and
found that the memory B cells induced by the AS04 vaccines were much
higher than those using aluminum hydroxide. This has been shown for both
HPV 16 and 18. Although the role of memory B cells is not clear in the
context of HPV, it is clear that induction of memory B cells at the end
of the primary vaccination course will help to maintain high antibodies
levels for a long period of time in the blood and the genital
mucosa.]{.mark}

[These results led to evaluation of the efficacy generated by the HPV
16/18-AS04 vaccine, and the persistence of the antibody response was
confirmed in this initial efficacy trial, HPV-001/007. Looking at
antibody responses, as measured by total antibodies by ELISA, for both
HPV 16 and 18, there was close to 100 percent seropositivity up to five
and a half years following vaccination. In terms of GMT titers, a peak
was observed at Month 7 and then a decline up to Month 18, but there was
a plateau from Months 18 onward both for HPV 16 and 18. At the end of
the follow-up period, antibody titers were more than tenfold higher than
those induced by natural infection. The graphs for HPV 16 and 18 are
nearly identical, when using a total ELISA assay as well as a
pseudovirion-neutralizion assay developed by NCI, where there was
exactly the same persistence of seropositivity, more than 98 percent at
the end of the follow-up and antibody titers for both HPV 16 and 18 that
were significantly higher than those induced by natural
infections.]{.mark}

[In evaluating the presence of antibodies in the genital mucosa in
different age groups, it was determined that there was a good
correlation between antibody levels in the serum and those in the
cervical mucosal centers for both HPV 16 and 18. This was at month 24,
when antibody levels in the serum had reached a plateau and there was
still protection.]{.mark}

[The efficacy trial was performed in women age 15 to 25 or older. Two
trials were conducted to bridge the younger age group, 10 to 15 years
old, and the older age group, 26 to 55 years old. In the immunobridge
study to the younger age group, the graphs are consistent and similar
for HPV 16 and 18: 100 percent seropositivity and GMTs around two times
higher in this population than in the 15-to-25 population, which
suggests that the vaccine will be able to induce long-term protection in
this population where it is most needed.]{.mark}

[For the older group, the age stratification was as follows: 15 to 25,
26 to 35, 36 to 45, and 46 to 55. Exactly the same picture was seen for
HPV 16 and 18: 100 percent seropositivity following vaccination course.
As expected, a decline in GMTs is seen with age, but even in the oldest
age range, antibody titers are still much higher than what is induced by
natural infection. These antibody titers are even higher than those
obtained at the plateau phase of the efficacy studies, which are
considered protective levels. This suggests that GSK's vaccine will be
able to counterbalance the immune decline in older age groups.]{.mark}

[In conclusion, AS04 was designed to enhance immunogenicity and increase
duration of protection. The clinical data generated substantiate this
enhanced immune profile in terms of sustained response, intensity of the
response at the site of infection, and in a broad age range. Antibody
responses are comparable for both HPV 16 and HPV 18. Including only 16
and 18 in the vaccine combined with AS04 has assured the best immune
response to both HPV 16 and 18 and potentially to the closely related
types 31 and 45, inducing long-term protection against cervical
cancer.]{.mark}

[]{.mark}

**[Bivalent HPV Vaccine Clinical Overview and Safety Review]{.mark}**

[]{.mark}

[Dr. Dubin noted that the GSK vaccine development program included two
efficacy studies, both of which evaluated vaccine efficacy against HPV
16 and 18 endpoints. The Phase II program, referred to as HPV-001, and
its extension phase, HPV-007, evaluated vaccine efficacy in a group of
women who were naïve for oncogenic HPV infections at baseline, a
population that approximates those targeted for public-health
vaccination: young adolescent girls who have not yet initiated sexual
activity and who have not yet been exposed to HPV. This study
demonstrated that the vaccine provided up to 100 percent protection
against HPV 16 and 18 endpoints, and this efficacy was sustained over
five and a half years of follow-up.]{.mark}

[The Phase III program, HPV-008, evaluated efficacy in a large cohort of
over 18,000 women who were not screened prior to study entry and who
therefore represent the more general population of women who might be
targeted for vaccination. Results confirmed that the vaccine was highly
efficacious against cervical precancers (CIN 2+ lesions) caused by HPV
16 and 18.]{.mark}

[These trials also assessed the vaccine's efficacy against other
oncogenic types. After HPV 16 and 18, the next most common HPV type
associated with cervical cancer is HPV 45, responsible for approximately
6.7 percent of cases. HPV 45 is phylogenetically related to HPV 18 and,
like HPV 18, is responsible for a significant portion of adenocarcinoma
cases, a particularly aggressive form of cervical cancer that often
escapes Pap smear detection or is detected too late. HPV 16/18 and 45
appear to have some unique properties in their potential to progress
from cervical precancers to cancers. These are the only three types that
actually cause a greater proportion of cervical cancer cases than cases
of high-grade squamous intraepithelial neoplasia. The next ten most
common HPV types are associated with about 22 percent of cervical
cancers. HPV 45 and HPV 18 are both members of the A7 species, along
with a few others. Five other types are related phylogenetically to HPV
16, and are members of the A9 species.]{.mark}

[In the Phase II studies, significant cross-protection was observed when
evaluating vaccine efficacy against individual virus types using
persistent infection as the definition. Using incident infection as the
virologic endpoint, significant cross-protection was observed against
HPV 45 over the entire five-and-a-half-year follow-up period. An
additional year of follow-up is coming very soon.]{.mark}

[Assessment of cross-protection can be extremely complex, due to
potential confounding effects of multiple infections, so in the Phase
III program, a more robust measure of efficacy for cross-protection was
used. Persistent infection avoids possible confounding effects and
allows direct determination of the impact of the vaccine on each of the
individual types. It will still be important to look at overall
aggregate effects against lesions, independent of any HPV types.
Persistent infection has been recognized by WHO as a valid endpoint for
assessment of cross-protection.]{.mark}

[GSK has found evidence of significant cross-protection against three of
the four individual oncogenic types that cause cervical cancer,
including HPV Types 45, 31, and 52. These evaluations were done in a
very broad cohort, with subjects that were non-naïve for other oncogenic
types at study entry, so it better reflects the general population.
Cross-protection was also assessed against the combination of all tested
12 additional non-vaccine oncogenic types using a 12-month definition of
persistent infection. This pre-specified analysis showed vaccine
efficacy of 27 percent against these12 viruses. This analysis was part
of the interim efficacy analysis for the primary endpoint in the study
and because of the timing, over 90 percent of the infections seen were
in subjects that had not yet received all three doses of vaccine. It is
expected therefore that with longer follow-up time these results might
increase.]{.mark}

[GSK has recently conducted exploratory analyses to evaluate
cross-protection in an HPV-naive cohort, a subset of almost 9,000 women
in the HPV-008 study population who were negative at study entry for a
panel of 14 oncogenic types and had normal cytology. Protection was
observed against HPV 45 alone, the combination of HPV 45 and 31, in
combined]{.mark} analyses, which included the five most common HPV types
associated with cervical cancer, with efficacy of 41 percent, and in
analyses that included the ten most common types stratified by their
phylogenetic relationships to either HPV 16 or 18. [Results indicated
significant vaccine efficacy against both HPV-related viruses.]{.mark}

[Dr. Dubin then described GSK's experience with the AS04 adjuvant in
other vaccine programs. AS04 is used in Fendrix, a licensed, adjuvanted
hepatitis B vaccine available in the European Union for use in
hemodialysis patients. AS04 is also used in the investigational genital
herpes vaccine program in large-scale Phase III clinical development. In
total, there are 40 completed studies and three ongoing studies in the
development programs for these vaccines, including over 26,000 subjects,
16,000 of which have received over 40,000 doses of AS04 adjuvanted
vaccine.]{.mark}

[AS04 adjuvanted vaccines have been generally well tolerated.
Injection-site symptoms are commonly reported, but are usually of short
duration and low-grade intensities. Rates of unsolicited symptoms were
carefully assessed, including serious adverse events, throughout the
entire duration of the trials and were similar in active AS04 vaccinees
and controls in each of the programs.]{.mark}

[Dr. Dubin summarized results from a large pooled safety analysis, which
represents the single largest cohort reported to date for analysis of
HPV vaccine safety, with data from over 29,000 women in 30 countries,
16,000 of whom have received the active HPV vaccine. The analysis
included all subjects that received at least one dose of vaccine. The
database represents a broad range of ages and an ethnically and
geographically diverse cohort. The trials were designed to collect
comprehensive safety data, especially for outcomes that might occur at
low frequencies.]{.mark}

[Information was collected on injection-site and systemic symptoms,
using diary cards over a seven-day period following each dose of
vaccine. Information was also collected on all unsolicited adverse
events for a period of 30 days following each dose of vaccine. Serious
adverse events and medically significant conditions were evaluated
during the entire follow-up period, which ranged up to five and a half
years. Medically significant conditions were defined as conditions that
prompted either physician or emergency-room visits. Outcomes of
pregnancies and the occurrence of new onset autoimmune diseases were
assessed throughout the trials.]{.mark}

[The entire cohort was stratified by age, baseline HPV 16 and 18
serostatus and baseline 16 and 18 DNA status. Naïve individuals were
defined as being seronegative and DNA negative for both of the vaccine
types. Currently or previously exposed individuals were defined as those
seropositive or DNA positive for at least one of the vaccine types and
currently infected individuals were DNA positive for at least one of the
vaccine types.]{.mark}

[Three different control preparations were used for comparison with the
HPV vaccine, depending on the phase of development and the age of the
target population. They included an adult formulation of licensed
hepatitis A vaccine, the pediatric formulation of the hepatitis A
vaccine for the adolescent studies, and aluminum hydroxide. Local
injection-site symptoms, such as pain, redness, and swelling, were more
commonly reported in vaccine recipients, however most of the symptoms
resolved after a few days, and the rates of Grade 3, or severe symptoms,
were very low. General solicited symptoms tended to occur at lower
frequencies than injection-site symptoms. Although the rates of some
specific symptoms, such as myalgia, were higher in the vaccine group,
the differences tended to be small and the rate of Grade 3 symptoms was
low.]{.mark}

[Similar patterns of reactogenicity were observed among subjects
stratified by baseline HPV 16 and 18, initial serostatus, or DNA status.
There did not appear to be any differences in the rate of local
injection-site symptoms according to the history of prior HPV infection
or current infection at the time of infection, either for all symptoms
considered at any intensity grades or Grade 3 symptoms alone. Similar
patterns of reactogenicity were seen in young adolescent girls and in
women over 25 years of age. The immunobridging data for these two age
groups were also similar: higher rates of local injection-site symptoms
compared to control, but low rates of Grade 3 symptoms.]{.mark}

[Regarding reporting at least one unsolicited symptom or medically
significant condition during the trials, rates observed in the HPV group
were very similar to the rates observed in the placebo and control
groups. There was no difference in the rate of serious adverse events
reported or the proportion of subjects that withdrew from the studies
due to either an adverse event of any intensity grade or serious adverse
event.]{.mark}

[In the pooled analysis, a total of five fatalities were reported; none
were considered related to vaccination. Although the individuals
remained blinded because they came from the ongoing Phase III efficacy
study, only one had received the HPV vaccine and the other four were all
hepatitis A controls.]{.mark}

[Since the majority of women targeted for vaccination will be of
childbearing potential and since autoimmune diseases tend to occur more
frequently in young women than in other demographic groups, GSK assessed
all pregnancies very carefully during the course of the studies and
prospectively solicited information on new onset of chronic diseases,
including autoimmune conditions. The rate of autoimmune diseases
reported in subjects that had received the HPV vaccine was very similar
to placebo or control groups. There were strict protocol requirements
for adequate contraception during the vaccination phase, but pregnancies
were allowed during the long-term follow-up periods. Overall, a fairly
large number of pregnancies was reported. However, rates of specific
pregnancy outcomes, such as miscarriages, abnormal infants, or
premature, were very similar in the active vaccine group compared to the
control groups in this pooled analysis.]{.mark}

[In conclusion, studies clearly demonstrate a very high level of
protection against HPV 16 and 18 endpoints, including CIN2+ lesions, as
well as efficacy against nonvaccine types. The vaccine is generally well
tolerated across all age groups; rates of unsolicited symptoms, serious
adverse events, autoimmune diseases, and pregnancy outcomes are
comparable in all of the analyses conducted to date, indicating a very
favorable safety profile.]{.mark}

[Since the HPV vaccine is now licensed in over 30 countries, GSK is
planning its Phase IV activities, including a long-term efficacy
follow-up for subjects enrolled in Finland in the Phase III program.
Finland has cancer registries that will show cancer outcomes many years
into the future. A large cohort study in adolescents and young adults is
being planned, which will assess safety outcomes, including autoimmune
diseases, pregnancy outcomes, and vaccine effectiveness. A large
community-randomized trial was recently initiated in Finland. This trial
will ultimately enroll over 70,000 subjects and will assess vaccine
effectiveness, induction of herd immunity, and potential impact of
vaccination on non-vaccine oncogenic HPV types, as well as safety and
pregnancy outcomes. After U.S. licensure is achieved, there will be a
pregnancy registry in this country. Meanwhile, GSK looks forward to
presenting results of the final analysis of the ongoing efficacy and
head-to-head trials.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Sumaya asked for clarification on the different types of tests used
to assess the antibody response to anti-HPV 18. Dr. Dubin explained that
each company used its own assays to evaluate vaccine immunogenicity over
time, so it is difficult to compare results. However, very high levels
of sustained seropositivity have been observed for both types over the
long-term follow-up. The head-to-head comparative trial should provide
the requested data. There is some preclinical data from a study on mice
that directly compared Gardasil and the GSK candidate vaccine head to
head. These analyses show, for HPV 18, a three- to fivefold difference
in geometric mean antibody titer several weeks following the two-dose
injection schedule used in mice. These data do indicate that there are
likely to be differences, especially in terms of HPV 18 immunogenicity.
Utimately the duration of protection may be dictated by the ability of
the vaccines to induce sustained antibody titers. Even though immune
memory needs to be considered as an important element in the immune
response, there are no clinical data to date that establish the role of
immune memory in providing protection for this particular disease. These
infections tend to occur very quickly, perhaps even before an anamnestic
response can impact the course of the infections.]{.mark}

[Dr. Schaffner asked whether there were any plans to immunize or study
the vaccine in males. Dr. Dubin replied that the Phase IV community
randomized trial in Finland would include evaluation of immunization of
boys, particularly whether vaccinating boys induces better herd immunity
than vaccinating boys and girls or females only. Results of modeling
suggest that if there is high coverage level in girls, there is likely
to be very little incremental benefit in cervical cancer protection by
vaccinating boys. However, policy groups will be meeting to determine
whether there is a role for male vaccination based on induction of herd
immunity.]{.mark}

[Dr. Judson noted that no one knows what the minimal effective
neutralizing antibody titer is, but that re-infections with the same
serotype seem to be extremely rare, based on natural history studies.
Dr. Dubin explained that two biological benchmarks were used in the
studies \-- the level of natural infection, which provides incomplete
protection, and the level of antibodies seen during the plateau phase of
the long-term efficacy study, which has provided complete protection. It
is thought that the threshold of protection will be somewhere between
those two biological benchmarks. In the long-term studies done to date
and in all of age ranges evaluated, titers for both types were sustained
above the higher protective threshold in the efficacy study.]{.mark}

[Dr. Iskander commented that in future presentations on reactogenicity
data, it would be helpful to use standard terminology to talk about
saline placebo versus aluminum placebo. It is also helpful to be able to
tease out components of reactogenicity that are attributable to the
adjuvant vs. other components. Dr. Neuzil added that it would also be
helpful to see one-, two-, and three-dose efficacy
presentations.]{.mark}

[]{.mark}

**[Outcomes Related to HPV 6/11: Recurrent Respiratory Papillomatosis
and Genital Warts]{.mark}**

[]{.mark}

[Dr. Unger summarized what is known about recurrent respiratory
papillomatosis or RRP, its natural history, risk factors, and burden of
disease. Respiratory papillomatosis is a descriptive name for papillomas
or warts in the upper respiratory tract. It is called recurrent
respiratory papillomatosis because recurrence is the rule and is
required for formal classification. The larynx is the most frequent site
of involvement and, within the larynx, the vocal cords. Protrusion of
these growths into the airway results in hoarseness and continued growth
can result in airway obstruction. Hoarseness and changes in voice
quality are the most common presenting signs. Diagnosis may be delayed
for several months to a year from the first symptoms, particularly in
children. Rarely, sudden death due to airway obstruction may be the mode
of presentation.]{.mark}

[There are two modes of onset of disease \-- in childhood, referred to
as juvenile onset, and in adults. The age of demarcation varies
somewhat, but age 18 is commonly used. Both juvenile and adult RRP are
associated with HPV 6 and 11. Diagnosis is apparent at endoscopy, as the
gross lesions have a characteristic but somewhat variable appearance.
Histologically, the papillomas are characterized by projections of a
thickened squamous epithelium with frequent koilocytotic changes that
are characteristic of a productive viral infection. HPV 6 and 11 can be
demonstrated by in situ hybridization. These lesions are histologically
benign.]{.mark}

[The goal in therapy is not to remove all lesions, but to preserve the
airway. Aggressive treatment can actually increase morbidity because of
damage to the vocal cords, quality of voice, and web formation.
Diagnosis and treatment occur in tertiary-care centers by
otolaryngologists. Obstructing lesions are removed with laser surgery,
microdebriders, or biopsy forceps. A variety of additional therapies and
adjuvant treatments are used. Lesions recur unpredictably and can spread
throughout the respiratory tree. Children are particularly susceptible
to sudden airway obstruction due to growths and intervening infections,
and tracheostomy may be required to maintain airways in these
situations.]{.mark}

[Spread below the larynx into the lower respiratory tract is a rare
event. In the lungs, these lesions appear as benign squamous lined cysts
that slowly enlarge and compromise lung capacity and result in
pneumonia. Rarely, malignant transformation has occurred. Successful
treatment of growth in the lungs has not been described.]{.mark}

[Intrapartum exposure to maternal genital HPV infection is the
implicated mode of transmission of juvenile onset RRP, despite the
median age of diagnosis at three years. None of the U.S. data on risk
factors are population-based, however, clinicians frequently cite the
classic triad of a teenaged mother, vaginal delivery, and firstborn
child. Young maternal age would be more likely to be associated with a
recent infection. Vaginal delivery would be associated with infant
exposure to genital secretions and firstborn associated with longer
delivery times and increased time of exposure. However, there are no
objective measures of the magnitude of these risks, and the rare outcome
in the face of high frequency of maternal infection argue strongly that
other factors are involved. Investigators are looking for genetic
susceptibility factors.]{.mark}

[Silverberg and colleagues conducted a retrospective cohort study to
evaluate the association between maternal and infant characteristics and
RRP, using data from Danish registries gathered between 1974 and 1983.
Among 1.2 million live births, investigators identified a little over
3,000 births among women with genital warts during pregnancy and 57
cases of juvenile onset RRP. Of these, 21 cases were born to mothers
with documented warts and 36 to mothers without, indicating maternal
warts as a significant risk factor. The relative risk of RRP was over
200. Nevertheless, the majority of RRP cases occurred in children whose
mothers did not have documented genital warts. Cesarean section was not
protective, although the low rate of C-sections in this population
limited the power to detect a difference.]{.mark}

[RRP is a very rare disease and most reports in the literature are case
series or anecdotal clinical experience. Juvenile-onset RRP or JORRP has
been studied more extensively than the adult-onset disease. The best
estimate of U.S. incidence and prevalence comes from a population-based
study in Seattle and Atlanta, conducted in 1996. Based on this study,
the estimated incidence of JORRP is between 0.4 and 1.1 per 100,000
person-years for children less than 18 years and prevalence is between
1.7 and 2.6 per 100,000 in children younger than 18 years. The1999 U.S.
Census figures would predict 80 to 1500 incident cases and 700 to 3,000
prevalent cases of JORRP in the United States.]{.mark}

[Based on the two-city study of incidence and prevalence, the CDC and
the RRP task force conducted a record-based registry of all children
less than 18 years of age treated at 22 tertiary-care centers throughout
the U.S.. It collected data on incident and prevalent cases seen between
1996 and 2002 to determine disease characteristics. The registry
included 603 children. There was no evidence of a male preponderance,
and slightly more than half had private insurance. In agreement with
case-report series, the median age at diagnosis was 3.1 years, with a
range of one month to 17 years. Age of diagnosis is not the same as the
age of onset, as substantial and variable delays occur between first
symptoms, sometimes diagnosed as croup or asthma and final
diagnosis.]{.mark}

[Because the registry was not population based, it did not provide
evidence of burden of disease in terms of incidence or prevalence, but
it did reflect the numbers of surgery required to manage the illness.
The mean lifetime number of surgical treatments was 13, with a range of
2 to 179. Regardless of the age of diagnosis, as the airway matured, the
numbers of surgeries decreased, reflecting the increasing size of the
airway. Nonetheless, age at diagnosis was a predictor of disease
severity, reflected by the likelihood of disease extension below the
larynx and requirement for a]{.mark} tracheostomy.

[Based on an analysis published by Bishai and colleagues and prevalence
data from the Atlanta-Seattle study, and updating the figures to 2006
costs, the estimated cost of a single case of JORRP would be almost
\$43,000 annually, which would correspond to about \$154,000 over a
lifetime. This translates to an annual cost of between \$19 million and
\$186 million for prevalent cases in the U.S.]{.mark}

[Even less is known about adult onset RRP (AORRP). The only reported
estimate of incidence is 1.8 per 100,000 person-years among people aged
greater than 15. This comes from a 1993 survey of American
otolaryngologists. However, a survey response rate of 23 percent and use
of analytic methods extrapolating the rates of respondents to 100% of
U.S. otolaryngologists suggests that 1.8 is a significant overestimate
of prevalence. There has been no attempt to estimate incidence. Risk
factors for AORRP have not been well studied, but orogenital
transmission during sexual activity is believed to be the mode of AORRP
acquisition. The two small case-control studies that looked at risk
factors suffer from limitations, but both reach the same conclusion that
the traditional risk factors for juvenile onset RRP were not active in
the adult form. One study did find significantly more lifetime sex
partners and more frequent oral sex among cases of adult onset RRP than
controls.]{.mark}

[]{.mark}

[Dr. Dunne provided information on HPV-associated genital warts. HPV
Types 6 and 11 are the primary cause of genital warts; one recent study
found that HPV 6 or 11 was detected in 97 percent of 65 genital-wart
specimens. HPV 6 was found in approximately 70 percent, HPV 11 in
approximately 40 percent, and both types were found in 10 to 20 percent
of specimens.]{.mark}

[Clinical presentation varies and includes flat warts, papules,
pedunculated, grouped warts or condylomas; clinical presentation may
vary based on the type of genital mucosa involved. Many cases go
unreported, as genital warts rarely cause symptoms such as pain. They
are, however, associated with frequent recurrences with or without
treatment, and usually recurrences cluster around the first detected
episode. For HIV-infected persons, warts may be larger, more numerous,
and more difficult to treat. During pregnancy, warts are more likely to
proliferate.]{.mark}

[The psychosocial burden due to genital warts is important. Diagnoses
cause anxiety, discomfort, embarrassment, anger, and shame, and these
emotions can adversely affect intimate relationships. One study
evaluating the psychosocial impact found significant distress was
associated with recurrences and treatments due to genital warts. In
addition, there was commonly a delay in seeking treatment.]{.mark}

[Treatments for genital warts are described as patient applied or
provider administered. They include antiproliferatives, such as
antimitotic treatment like podophyllin; destructive or excisional
treatments, such as cryotherapy, excision or laser treatments; and
immunomodulating treatments, such as imiquimod, a therapy that induces
an immune response to warts. Treatments can result in side effects,
including burning, itching, pain, and, rarely, fistulas or ulcers.
Episodes of care last, on average, for three clinic visits, and 70
percent of the cases are concluded within a ten-week period.]{.mark}

[Transmission is by sexual contact, primarily through sexual
intercourse. A study conducted in 1971, before the etiology of genital
warts was known to be HPV, found that as many as 64 percent of the
sexual contacts of men or woman with genital warts acquired the disease.
On average, the acquisition of genital warts after sexual contact was
2.8 months. A recent study conducted in a cohort of college women in
Seattle demonstrated the high acquisition of genital warts. The study
evaluated women who had incident HPV 6 or 11 infection and followed them
for development of warts. By 24 months, approximately 60 percent of the
women with incident HPV 6 or 11 infections developed genital warts. The
median time between detection of incident HPV 6 or 11 infection and
detection of the genital warts was 2.9 months, and the median time to
clearance with treatment was 5.9 months.]{.mark}

[There are imprecise estimates of the burden of genital warts in the
United States because there are no nationally representative data and
the disease is not nationally reportable or notifiable. Previously
experts estimated that 1 percent of sexually active individuals had
genital warts. The best available data are from large databases on
insurance claims, including Medstat and Integrated Healthcare
Information Services (IHCIS); National Health and Nutrition Survey
(NHANES), a nationally representative sample of the U.S. population; and
clinic data from the STD Surveillance Network, a network of sentinel STD
clinics in the U.S. in five geographic regions. None of these data have
prevalence or incidence of disease from a nationally representative
population, but all offer some insight on the burden of disease. The
National Disease and Therapeutic Index (NDTI) uses physician reporting
to assess prevalence and incidence, but there are wide standard errors
of estimates.]{.mark}

[An evaluation of genital warts using administrative discharge data was
conducted in Medstat, a national insurance-claims database. The results
showed the highest rate per 1,000 person-years occurred in the 20- to
30-year-old females and males and the peak occurred at a younger age in
females than males. However, the overall rate in person-years was
similar for males and females at 1.7 per 1000 person-years.]{.mark}

[The IHCIS database is a collection of claims data from 1.7 million
members from 30 health plans and it showed that the rate of new
genital-wart claims was 157 per 100,000 person-years, with age-specific
differences. Both Medstat and IHCIS demonstrate a similar incidence of
genital warts, half a million cases per year, with a range of 200,000 to
1 million cases and clear age-specific differences in prevalence and
incidence.]{.mark}

[There are limitations to these administrative databases. Data on
prevalence are among an insured population, and detection requires an
office visit. Other studies have shown that many who have genital warts
do not seek treatment or healthcare. In addition, the discharge codes
can be nonspecific for genital warts.]{.mark}

[During 1999 to 2004, there was an NHANES assessment of genital warts.
Sexually active men and women were asked the question, \"Has a doctor
ever told you that you had genital warts?\" Prevalence of ever having
been diagnosed with genital warts was higher in women (7.2 percent) than
men (4 percent) and highest among the 25- to 34-year-old women and 35-
to 44-year-old men. STD clinic data suggest genital warts are one of the
most common STD diagnoses, and are typically more common in men than
women, which likely reflects the population attending STD clinics. The
STD Surveillance Network evaluated prevalence of genital-wart diagnosis
in 17 STD clinics in five geographic areas. Although it varied by
geographic area, a substantial proportion of visits were for genital
warts: between 1.7 and 13.6 percent of all visits.]{.mark}

[HPV vaccination could reduce the costs associated with genital warts.
The primary factors that drive cost-effectiveness evaluations are direct
medical costs, including cost of treatment; repeat visits for treatment;
and quality of adjusted life years, or QALYs. The short-term reduction
in QALYs associated with genital warts has been estimated to be
approximately ten percent. However, there are limited studies and this
estimate is primarily based on expert opinion. An important
consideration for HPV vaccine cost-effectivenes is the issue of
discounting, whereby benefits that accrue earlier are valued more highly
than benefits that accrue later. The impact of the HPV vaccine on
genital warts would be earlier than for cervical cancer and some
cervical cancer precursor outcomes.]{.mark}

[The annual direct healthcare costs of genital warts in the U.S. are
estimated to be \$200 to \$225 million. The cost for a treated case of
genital warts is \$567, which includes treatment and repeat visits
required due to recurrences or to complete treatment. Treatment costs
using commonly prescribed therapies range between \$150 and \$2400, and
repeat visits for office treatments are, on average, three visits over a
three-month period.]{.mark} The percentage of total averted costs in
QALYs saved by HPV vaccination attributable to reductions in genital
warts is about 12 to 13 percent.

[In summary, there are imprecise estimates of prevalence and incidence
of genital warts in the U.S. Available data suggest an incidence on the
order of half a million cases per year, with a range of 200,000 to 1
million. The incidence and prevalence varies based on ages being
considered. Genital warts are common in young women and men, and the
peak prevalence is in 20- to 30-year-olds. There is a substantial health
and economic burden due to genital warts.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Chilton asked whether the fact that lifetime costs for treatment of
respiratory papillomatosis were less than four times the annual costs
implied that the average life expectancy is less than four years. Dr.
Chesson replied that the cost estimates by Dr. Bishai assumed a 4.2 year
duration of the cost associated with RRP, which does not assume death at
four years, just the end of the costs. Dr. Schuchat added that the need
for surgery decreases with age, so the frequency of surgery is weighted
early in the life.]{.mark}

[Dr. Katz asked how measles vaccine worked in treating RRP. Dr. Unger
replied that there had been no placebo-controlled comparison. It is
given by one clinician, who does not know why it works and in fact there
is controversy about whether it really does work. Most people posit that
it is an adjuvant effect.]{.mark}

[]{.mark}

**[Issues for ACIP Consideration]{.mark}**

[]{.mark}

[Dr. Markowitz reminded the ACIP that in June 2007 there was the first
update on the Phase III data from the bivalent HPV vaccine and an
introduction to considerations for ACIP recommendations. Today there
were presentations on background data that the committee will need for
recommendations. Proposed sessions for February would include an
overview of the vaccine data and other data that may become available,
along with cost-effectiveness analyses of the two vaccines and then a
potential vote on the bivalent HPV vaccine.]{.mark}

[ACIP currently recommends routine vaccination of females with
quadrivalent HPV vaccine at 11 to 12 years of age. Vaccination can be
started as young as nine years of age and is recommended for females 13
to 26 years of age who have not been previously vaccinated or completed
a full series. There are a variety of special situations, including
equivocal or abnormal Paps, positive HPV test, or genital warts.
Vaccination would provide protection against vaccine types not already
acquired, but will have no therapeutic effect. Immunocompromised
patients can be vaccinated, although the immune response and vaccine
efficacy might be less in this group. Quadrivalent vaccine can be
administered at the same visit as other age-appropriate vaccines. There
were no data on administration of the quadrivalent vaccine with vaccines
other than hepatitis B vaccine at the time of licensure, but it is not a
live vaccine. The vaccine is not recommended for use in
pregnancy.]{.mark}

[Questions under consideration are related to the bivalent vaccine
itself and to having two licensed HPV vaccines. First, what
recommendations should be made for bivalent vaccine use in 10- to
25-year-old females, assuming this is the age for which it is licensed?
If it is licensed for use in older females, what recommendations should
be made in that age group? Possible ACIP recommendations are for
vaccination of 11 to 12 year olds, similar to the quadrivalent vaccine.
It could be given as young as ten years of age, with catch-up
recommended for 13 to 25 year-olds. For the special situations and
pregnancy, the possible ACIP recommendation would be similar to the
quadrivalent vaccine.]{.mark}

[Regarding simultaneous vaccination, there will be no data on
administration with any vaccine at the time of licensure, although
studies are ongoing. Although it is not a live vaccine, and the general
recommendations state that non-live vaccines can be given simultaneously
with other vaccines, the bivalent HPV vaccine contains a new adjuvant.
The options are either not recommending simultaneous administration
until further data are available or stating that the vaccine can be
administered simultaneously.]{.mark}

[It is not clear whether there will be a FDA indication for use of the
vaccine in older women based solely on immunobridging data. Efficacy
trials are ongoing for both the quadrivalent and the bivalent vaccines.
If there is an indication, the work group is discussing a variety of
options, including a permissive recommendation in some specific age
groups, recommendations for specific subgroups, or other
recommendations.]{.mark}

[For two licensed HPV vaccines, issues that need to be addressed are: 1)
Should a preference be stated for one vaccine? Data to be considered for
this issue include: Are there differences related to protection against
HPV 16 and 18 outcomes, differences related to protection against
outcomes related to other oncogenic types, or differences related to
protection against HPV 6 and 11? Are there differences in cost-
effectiveness between the two vaccines? 2) Can the vaccines be used
interchangeably, i.e., can vaccination series be started with one
vaccine and completed with another?]{.mark}

[Dr. Markowitz reviewed summary data comparing the two vaccines. In
terms of protection against HPV 16 or 18, CIN, or AIS endpoints, the
working group feels that both vaccines are similar and have very high
efficacy. For the quadrivalent vaccine, there are additional data
showing it is effective against VIN and VaIN. For HPV 6- and 11-related
genital lesions, quadrivalent vaccine provides protection but the
bivalent vaccine does not. For cross-protection against high-risk types
other than HPV 16 and 18, it is still somewhat unclear because the
endpoints used are different. The work group feels that both vaccines do
provide some cross-protection, although it may be limited. The overall
impact of cross-protection might be similar between the two vaccines,
although it could differ slightly for specific types. At the present
time, there are no data to indicate differences in duration of
protection. Efficacy has been very high for both vaccines and they
appear similar at the present time, but this remains a question.]{.mark}

[The quadravalent vaccination series will cost \$360; pricing for the
bivalent is still unknown. Cost-effectiveness will be reviewed at the
next ACIP meeting. All else being equal, the quadrivalent vaccine that
provides protection against 6 and 11 would be somewhat more
cost-effective, but differences in any of the other attributes could
change the relative cost-effectiveness.]{.mark}

[The work group has not crafted specific recommendations related to
having two licensed HPV vaccines, but has discussed stating differences
in the data available for the two vaccines to date, specifically with
regard to protection against HPV 6 and 11, and noting that the
quadrivalent vaccine provides protection against genital warts. This
would encourage providers to understand differences between the two
vaccines. For protection against 6/11/16/18-related outcomes, the
quadrivalent vaccine would be recommended, and for protection against
HPV 16- and 18-related outcomes, the quadrivalent or the bivalent
vaccine would be recommended.]{.mark}

[Regarding a preferential recommendation, this is a very unique
situation, since one vaccine provides protection against additional
outcomes. There are knowns about both vaccines, and some of the
attributes may favor one vaccine over the other, but that will not be
known for several years.]{.mark}

[In terms of interchangeability of the two licensed vaccines, the work
group discussed stating that, whenever feasible, the same brand of HPV
vaccine should be used for all doses of the vaccination series. If the
vaccine previously administered is unknown, either HPV vaccine should be
used to continue or complete the vaccine series to provide protection
against HPV 16 and 18.]{.mark}

[The work group will be reviewing an enormous amount of data and
discussing issues related to recommendations for the bivalent vaccine
and for two licensed HPV vaccines, in preparation for a possible vote on
the bivalent vaccine in February 2008.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Neuzil suggested some additional considerations for the work group.
The presentations have talked about clinical trials with highly select
populations where women follow very strict schedules and the majority
get three doses. It will be very important to know how these vaccines
perform when not given on strict schedules and people do not get three
doses and it is given to the entire population.]{.mark}

[Dr. Judson added that it would also be helpful for clinicians and
patients who need to understand the costs and benefits of the vaccines
to know the age-specific prevalence rates within a certain margin of
error for different age groups with different sexual histories. Dr.
Markowitz said that some of these issues have been presented and
discussed at previous ACIP meetings before recommendations were made for
the quadrivalent HPV vaccine; the committee did not want to make
recommendations based specific sexual histories.]{.mark}

[Dr. Schaffner noted that those who are interested in adult immunization
have been encouraging the committee to move away from risk-based
immunizations to larger, age-based recommendations.]{.mark}

[]{.mark}

**Immunization Safety**

**Dr. John Iskander, CDC/OD/OSCO**

**Dr. Bill Thompson, CDC/NCIRD/ID**

**Dr. Barbara Slade, CDC/OD/OSCO**

**Dr. Sandra Chaves, CDC/NCIRD/DVD**

**Introduction**

Dr. Iskander introduced the three presenters and their topics.

**Early Thimerosal Exposure and Neuropsychological Outcomes at 7-10
years**

Dr. Thompson presented results from a published study on early
thimerosal exposure and neuropsychological outcomes at seven to ten
years. Thimerosal is a preservative used in many childhood vaccines
during the 1990s. It is metabolized into ethylmercury and thiosalicylate
and is 50 percent mercury by weight. Little is known about the potential
harmful effects of low-dose ethylmercury exposure from vaccines and
immunoglobulins. More is known about prenatal methylmercury exposure
from fish consumption.

The study was designed with significant input from independent, external
experts. The analysis plan was written and approved in 2002 prior to
data collection. All statistical analyses were executed as specified in
the analysis plan; subsequent to reviewing the first round of results,
additional analyses were conducted based on input from the external
experts.

This was a retrospective cohort study of children from four Vaccine
Safety Datalink (VSD) sites, who were born between 1993 and 1997 and
could have received thimerosal-containing vaccines. They were aged 7 to
10 years at the time of the neuropsychological testing, and were
stratified by thimerosal exposure during the first seven months of life,
using the automated VSD vaccine records.

Forty-two different outcomes were assessed during a three-hour testing
period. Autism was not assessed; there is a separate ongoing autism
case-control study. The study measured speech and language,
verbal-memory, attention and executive-functioning,
behavioral-regulation, fine-motor coordination, tics, general
intellectual functioning and achievement, and visual spatial-ability.
Measures were selected based on Tom Verstraeten's VSD screening study
and the methylmercury fish studies, as well as suggestions by the
external panel of consultants. Sources of information included VSD
automated data, which provided data and information on postnatal vaccine
exposures; medical-chart reviews of all the children and the mother\'s
prenatal records; vaccine records brought in by parents; and a maternal
interview regarding potential prenatal exposures.

For each outcome in the primary model , a prenatal thimerosal exposure
variable and a thimerosal exposure from zero to seven months variable
were defined. Adjustments were made for site variables, child and family
characteristics, and other exposures and confounders. An expanded model
included the prenatal thimerosal exposure variable and a thimerosal
exposure from 0 to 28 days variable, based on concern that very early
exposure was potentially problematic. That same model also included
thimerosal exposure from one to seven months. The published manuscript
presents results from 378 statistical tests, representing 42
neuropsychological outcomes and three exposure periods: the prenatal
period, the zero- to seven-month period; and the 0-to-28-days period.
Models were run for the entire sample as well as gender-specific
analyses.

A total of 1,107 children were tested in the clinics, representing a 30
percent response rate. After excluding children for conditions found
during parental interviews, the final analysis sample had 1,047
children. This provided power of 90 percent to detect 0.10 of a
standard-regression coefficient, which was more power than the
methylmercury fish studies had.

The majority of outcomes had no association with thimerosal exposure.
There were 12 outcomes where increasing thimerosal exposure was
associated with better outcomes, and 7 outcomes where increasing
thimerosal exposure was associated with poorer outcomes. This represents
significant findings for 5 percent of the statistical tests conducted.
For the prenatal exposure period, a better outcome was found for the
NEPSY Speeded Naming Test and a poorer outcome for the WISC III Digit
Span Backward Recall. For the birth to seven-month exposure period,
better outcomes were found on Grooved Peg-Board Non-Dominant Hand and
the WISC III Digit Span Backward Recall and no poorer outcomes were
found. For the birth to 28-day period, better outcomes were found on
Finger-Tapping Dominant-Hand and poorer outcomes for the Goldman-Fristoe
Test of Articulation.

In terms of the sex-specific effects, for the prenatal period in males
better outcomes were found for the Stanford Binet Copying and poorer
outcomes for the WISC III Digit Span Backward Recall; there were no
significant effects for the prenatal period for females. For the
birth-to-seven-month period, better outcomes were found in males with
the WISC III Letter-Word Identification and poorer outcomes with the
BRIEF Parent Rating of Behavior Regulation, and motor tic and phonic
tics, as reported by the child assessor. For females, there were better
outcomes for Grooved Peg-Board Non-Dominant Hand and the WISC III Digit
Span Backward Recall. For the birth-to-28-days period, better outcomes
were found on three measures for the males; for females, better outcomes
were found on motor tics based on the parent reporting and a poorer
outcome was found on the WASI Verbal IQ measure.

Among the 42 outcomes, few significant associations with thimerosal
exposure were found prenatally or during the first seven months of life.
These few associations were equally divided among better and poorer
outcomes and were mostly sex specific. The negative association for tics
is potentially important because a similar association was found in two
previous vaccine safety studies: Tom Verstraeten\'s 2003 VSD screening
study and the Andrews study in the U.K. Further study is needed.

The other negative associations were a poorer outcome with verbal IQ
among girls and the GFTA measure amongst all children, which suggest a
possible association with language development. This association was
also found in one HMO in the Verstraeten-VSD screening study. However,
the present study found a better outcome for performance IQ for boys,
which suggests that the finding cannot be generalized.

In conclusion, the weight of the evidence does not support a causal
association between early ethylmercury exposure from
thimerosal-containing vaccines and immunoglobulins and
neuropsychological functioning at seven to ten years of age.

As part of this study, a public-use data set was created and made
available on the CDC Web site the day the manuscript was published.

**Discussion**

Ms. Stinchfield asked for clarification on the immunoglobulin part of
thimerosal exposure. Dr. Thompson explained that if a pregnant mother
was rH negative she received immunoglobulins, which contained
thimerosal.

Mr. Lassiter asked why this study did not compare a no-thimerosal group
versus a thimerosal group, since there is no established toxicity limit
for ethylmercury. Dr. Thompson replied that very few children in HMOs
had received no thimerosal-containing vaccines at the time of the study.
Instead the study looked at a range of exposures, from low to high. A
study currently being carried out in Italy had a similar test battery
and randomly assigned children to thimerosal exposure and no-thimerosal
exposure. CDC also has an ongoing thimerosal-autism study, which should
be completed in the next year.

Ms. Redwood observed that this was just an observational study and not
designed to address causation and effect. The small sample size and few
children in the highest and lowest exposure groups reduced the study\'s
power and ability to establish statistical significance. Early
interventions, which may have reduced or eliminated deficits such as
speech delays by age seven to ten years, were not controlled, and there
was no analysis of combined prenatal and postnatal mercury exposures. In
addition, newborns weighing 5 lbs 8 ounces or less, approximately 9
percent of all U.S. births, were excluded. These infants may be more
vulnerable to mercury effects due to their smaller size. The study did
find associations similar to those detected in similar studies, such as
an increased rate of motor and verbal tics, and poor language ability,
which are also seen in autism. Replication of these same findings in two
other thimerosal investigations supports arguments for causality. These
findings were downplayed because several areas, including performance
IQ, letter and word identification, were enhanced by thimerosal
exposure. Children diagnosed with neurodevelopmental delays typically
have scatter skills. The fact that there are both detrimental and
beneficial findings from exposure to thimerosal does not equate with no
evidence of injury.

**Summary of Syncope Reports to VAERS**

Dr. Slade presented a summary of postvaccination syncope events in young
women after receiving the HPV vaccine, as reported to Vaccine Adverse
Event Reporting System (VAERS) from January 1, 2005, through July 31,
2007. Syncope is a transient loss of postural tone and consciousness
with spontaneous recovery. It is generally thought to be due to an
abnormal sympathetic reflex resulting in bradycardia, peripheral
vasodilation, and hypotension with decreased brain profusion. It can be
elicited by a variety of stimuli and has been documented to occur after
medical procedures, including vaccination. The ACIP recommends that
providers strongly consider observing patients for 15 minutes after
vaccination. If syncope occurs, the individual should be observed until
symptoms resolve.

Post-marketing safety is monitored through the VAERS, a national passive
surveillance system jointly operated by the FDA and CDC. It covers all
licensed U.S. vaccines and receives about 15,000 reports each year.

The objectives of this analysis included describing trends and syncopal
events reported in VAERS, characterization of the post-vaccination
syncopal events, and identification of potential areas for further
study. Serious reports of syncope have been reported, including death.
As an example, a15-year-old male who had received hepatitis B vaccine
had syncope, fell, hit his head, had cerebral hemorrhage, and
subsequently died. Eighty-nine percent of previously reported syncopal
events occurred within 15 minutes of vaccination. Of the 3,168 syncope
reports from 1990 through 2004, 35% occurred among persons aged 10 to
18, and 14% resulted in hospitalization, primarily due to injury from
the fall or for medical observation.

This study used MedDRA coding terms for "syncope" and "syncope
vasovagal." Cases had to be age five years or older. Vaccines reported
to be temporally associated with the syncope were identified and medical
records were reviewed for selected reports.

During 2002-2004, there was a total of 23,934 reports, with 203 reports
of syncope. For the study period (January 1, 2005- July, 31 2007), there
were 25,861 reports to VAERS, with 463 cases of syncope, a statistically
significant increase. In comparison, for serious syncope, there is no
statistically significant difference of the percentage of serious cases
of syncope between the two time periods.

The increase in syncope reports started in 2005, with a greater increase
late in 2006, and a marked increase in 2007, particularly for females
aged 11 to 18 years. This time frame parallels ACIP votes to recommend
the three new adolescent vaccines: MCV4, Tdap, and HPV. Of 463 syncope
reports, 49% were seen in females aged 11 to 18 years of age; the excess
reports among females, especially the 11- to 18-year-old age group, were
attributable to the HPV vaccine.

The top three vaccines associated with syncope reports in VAERS for the
study period were HPV, MCV4, and Tdap. At least one of these vaccines
was reported in 60% of the syncope reports for single vaccines and 68%
of reports for multiple vaccines. HPV was the most frequently reported
vaccine type. The numbers for the multiple vaccines are not
exclusionary, so there was overlap in the vaccines.

There were 41 syncopal reports associated with injuries among the 463
syncope reports. Thirty-one, or 76%, were among adolescents aged 11 to
18 years of age, and 71 percent were among adolescent females. The time
lag from vaccination to syncope onset was less than five minutes in 49%
of the cases and less than 15 minutes in 80%. Twenty-four percent or 10
of the injuries were characterized as serious due to hospitalizations
related to injuries from falls. An example is a 13-year-old girl who
fainted less than ten minutes after receiving both HPV and MCV4. She
fell backwards, hit her head, and was admitted to the PICU for a skull
fracture and subarachnoid hemorrhage. She has fully recovered.

Among individuals over age 50, there were 20 serious reports,
predominantly in females, including two deaths, one from anaphylaxis and
one from a hypoxic ischemic encephalopathy with multiple organ failure.
But 70% of the serious reports had pre-existing medical conditions,
primarily cardiovascular, and most of the cases were related to TIV,
including the two deaths associated with TIV. Of concern is that only
30% of the reported events occurred within the 15 minutes after
vaccination.

There are a number of limitations to the VAERS data. Incidence rates
cannot be calculated because the number of doses actually administered
is unknown. There is known underreporting of adverse events. The MedDRA
coding terms are used for indexing rather than for diagnosis, and
miscoding or misdiagnosis are not infrequent. All of the non-serious
reports were not reviewed, so it cannot be determined whether the
syncope was related to the particular vaccine, the age of the recipient,
or both. VAERS is not set up to do root-cause analysis, and one cannot
evaluate the impact of the fact that HPV has three doses rather than a
single dose.

In conclusion, there has been an increase in the number of syncope
reports in VAERS since 2005. This increase was associated with females
aged 11 to 18. Most were non-serious reports and were related to the new
"adolescent vaccines": HPV, MCV4, and Tdap. Injuries after syncope are
rare, but do occur and can be serious. These injuries may be
preventable, and the time interval for syncope after vaccination may
differ for different age groups.

Areas for further research include determining the age-specific
incidence rates for syncope associated with vaccination; a survey of
providers to evaluate adherence to the 15-minute recommended waiting
period after vaccination; studies to evaluate the effectiveness of this
waiting period and other measures to prevent secondary injury; and
evidence-based recommendations for interventions to prevent or predict
syncope after vaccination.

**Discussion**

Dr. Chilton noted that children under age five were excluded from the
study, yet the recommendations both from the AAP and the ACIP are to
have all children wait 15 minutes after an immunization. Dr. Slade
explained that younger aged children do not tend to have falls after
syncope.

Dr. Lett pointed out that some anecdotal evidence or published studies
showed an association between under-hydration and maybe hypoglycemia,
lack of food intake prior to syncope. Dr. Slade replied that that area
needed study. The Red Cross has started giving people a bottle of water
while standing in line to donate blood. In the non-serious reports, some
people commented that they had not eaten that day, which could cause
syncope. The literature reports that approximately 90% of people who
have an episode of syncope have a first-degree relative who also has
experienced syncope, so that could be a useful question to ask before
vaccination. While approximately 50% of people report having experienced
syncope at some time in their lives, people who have a history of more
than two episodes are very likely to have another one, so that could be
an additional question to ask before vaccination.

Dr. Baker asked if there was a study to define the missing areas, e.g.,
age-specific rates or potential interventions. Dr. Slade responded that
an on-going Vaccine Safety Datalink Project (VSD) study with the HPV
will be able to look at age-specific rates. A possibility is that CDC's
Clinical Immunization Safety Assessment Network (CISA) could do a study
looking at effectiveness of other interventions. Dr. Baker said that the
amount of pain reported from HPV suggests the syncope is probably a
vasovagal phenomenon.

Dr. Craig asked if there was any way to tease out the issue of something
in the HPV versus just the pain issue, even with the numbers being
relatively small. Dr. Slade replied that this would be difficult, but
that allaying people's fears while they are in the waiting room would
probably be helpful.

Dr. Salisbury indicated that the U.K. had resisted stating any length of
time that people should stay after vaccination, since keeping people
would be very inconvenient in a clinic. He suggested that reports of
convulsions and seizures needed to be studied as well. The U.K. has
found that what are reported as seizures occurring immediately after
vaccination are often just a form of fainting, so if using only syncope
as an indicator, a number of other instances may be missed. Dr. Slade
added that there are guidelines on how to tell the difference between
syncope and a real seizure.

Dr. Iskander noted the relative lack of an evidence base for either the
currently recommended interventions or any other interventions.
Postvaccination syncope falls into a patient-safety model, where the
need is to develop and design and evaluate interventions rather than
simply to continue to accumulate data on the problem.

**Update on Varicella Vaccine Safety**

Dr. Chaves reminded the committee that varicella vaccine for children
has been in routine use since 1995, and has resulted in a substantial
reduction in disease burden, mortality rate, and health
characterization. Early post-marketing data indicated that the vaccine
had a safe profile. Most of the reported adverse events were not
serious: mainly fever, varicella-like rash, and injection-site reaction,
which were described during pre-licensure clinical trials. The rare
serious adverse events reported were described as vaccine Oka strain and
included pneumonitis and hepatitis, both in immunocompromised patients,
as well as herpes zoster, secondary transmission, and severe rash post
vaccination. Encephalitis, ataxia, thrombocytopenia and vasculitis were
also described but there was no lab confirmation.

Since 1998, there has been a fivefold increase in the amount of
varicella vaccine distributed in the U.S., which could help identify
more rare adverse events. In addition, many adverse events were being
reported in the literature as case reports. Finally, there were concerns
about the late reactivation of the latent varicella vaccine virus.

The analysis used VAERS data from May 1995, when the vaccine was
licensed, to December 2005, and looked at all adverse events reported as
following varicella vaccine using all COSTART codes. It also searched
text fields specific for zoster and meningitis. Serious reports involve
hospitalization, death, and life-threatening and disabling illness.
Reporting rates were based on rates of vaccine distribution.

Results were similar to what was published in 1998 \-- the overall
reporting rate was 52.7 per 100,000 doses and the rate of reported
serious adverse events was 2.6 per 100,000 doses, roughly 5% of the
total. Fifty-eight percent of all reports followed varicella vaccine
administered alone and the majority were also soon after the vaccine was
licensed, dropping considerably over the next few years. There were
25,306 reports following varicella vaccine received and the most common
events were rash, fever, and injection-site reactions, followed by
urticaria and zoster.

Among all adverse events following varicella vaccine administration, a
total of 60 deaths were reported, for a rate of 0.1 per 100,000 doses
distributed. The majority of death reports had alternative diagnoses or
very little data were available to make any judgment in terms of
causality or association with the vaccine. Four cases are worth
mentioning. One published in 2003 was a vaccine strain VZV associated
with varicella pneumonitis in a child later identified as having natural
killer T-cell deficiency. The paper described the vaccine as a
contributing factor in his death. Two cases of encephalopathy due to
ornithine transcarbamylase (OTC) deficiency were identified in this
analysis. These were previously healthy children who received the
vaccine and then 14 and 30 days later developed ataxia followed by
encephalopathy; they were subsequently diagnosed with OTC deficiency.
OTC deficiency has a variety of triggering factors, including viral
infections, so the vaccine could play a role in activating this disease.
The fourth case died from hemophagocytic lymphohistiocytosis or HLH
diagnosed following receipt of varicella vaccine. HLH has also been
described as being triggered by a variety of viral infections. This
case's brother had died two years earlier from the same disease
following vaccination, but there was no record whether the vaccine was
varicella. Further investigation is needed to confirm these findings and
evaluate to what extent varicella vaccine could play a role in
activating diseases in persons with genetic predisposition.

There were 981 reports for zoster and 47 were serious enough to be
hospitalized, roughly 5% of the total. The median age was 2.5, ranging
from 12 months to 12 years, and the median interval from vaccination to
zoster was 7.3 months. The most frequent zoster location was the face,
and 12 cases had meningitis concomitantly. Twenty-eight of the 47
hospitalized children had PCR VZV positive, with ten confirmed as
vaccine strain and seven as wild type; 11 had not been genotyped. Most
of these children were healthy; only seven had any kind of
immunosuppressed illness described in their medical charts.

Among the 12 cases that had meningitis concomitantly, nine had VZV PCR
done in cerebrospinal fluid (CSF) samples. They were all children 1 to
12 years of age and most of them were healthy. The three isolates sent
for typing were all confirmed to be vaccine strain. Two were in
immunosuppressed children, and one was in a healthy child. After this
analysis was finished, another report was received of a healthy
eight-year-old, vaccinated at age four, who had zoster followed by
meningitis four days later. Both CSF and skin samples were VZV positive
by PCR and confirmed to be vaccine strain.

These results should be interpreted with caution. Because VAERS is
passive surveillance, underreporting is an issue, principally because
adverse events are more likely to be reported soon after the vaccination
(e.g., diseases related to varicella vaccine virus reactivation may take
years to occur). There is large number of reports soon after a vaccine
is licensed due to enthusiasm and awareness, but as soon as the vaccine
becomes routine, there is a drop in adverse events reported, which may
contribute to underreporting. Over-reporting can also be an issue as
many reports temporally related to vaccine are actually caused by other
agents. There is also the challenge of dealing with multiple vaccines
administered simultaneously. Most reports are not verified and very
limited clinical and lab data are available. Finally, there is no
denominator on doses administered by age, which makes it difficult to
estimate specific rates to compare findings with data available in the
literature.

Overall the vaccine has a good safety profile. The majority of adverse
events reported are non-serious. Many adverse events reported could be
biologically associated with the vaccine. The rate of zoster
reactivation among vaccinees is unknown, but limited data available seem
to suggest a lower rate of zoster among vaccinees compared with children
that had natural varicella disease.

There is little information on rates of rare complications with zoster;
recent studies, mainly in Europe, suggest this may be more common than
previously thought, but may also be just a reflection of lab tools
available in recent years.

In conclusion, overall serious events reported after varicella
vaccination continue to be rare, which is reassuring for the program,
and must be considered relative to the substantial benefits of the
varicella vaccination. The vaccine strain may be a contributing factor
in activating diseases in patients with genetic predispositions and may
also reactivate and cause serious zoster, leading to hospitalizations
and neurological complications, such as meningitis in healthy children.
Healthcare providers should be constantly reminded of the importance of
relying on lab results for diagnosis confirmation. CDC is planning to
develop communication materials to emphasize the importance of
laboratory confirmation and analytical studies to assess the risk of
zoster reactivation in vaccinees using Vaccine Safety Datalink.

**Discussion**

Dr. Katz asked whether the adult zoster study had any cerebrospinal
fluid spinal fluid findings of vaccine virus. Dr. Seward said she was
not aware of any, nor was she aware of any zoster cases confirmed to be
due to vaccine strain.

Dr Haber made a clarification about underreporting in new vaccine. What
drops is the number of the non-serious reports, but serious reports
remain steady over time in VAERS.

Dr. Iskander pointed out that one VAERS presentation used the COSTART
coding system whereas another used MedDRA (Medical Dictionary for
Regulatory Activities), which is actually the new international standard
and was adopted by VAERS in January 2007. From now on, the vast majority
of the data from VAERS should be using the MedDRA coding system.

**Rotavirus Vaccines**

**Dr. Lance Chilton, ACIP WG Chair**

**Dr. Leonard Friedland, GlaxoSmithKline**

**Dr. Margaret Cortese, CDC/NCIRD, DVD**

**Ms. Penina Haber, CDC/ISO/OSCO**

**Working Group Update**

Dr. Chilton said the group was reviewing information on two vaccines:
the currently licensed RotaTeq, the human reassortant vaccine and a new
GSK attenuated monovalent human rotavirus vaccine, Rotatrix, for which
FDA approval is expected sometime in the spring. The working group will
propose recommendations for the ACIP to consider if and when Rotarix is
licensed and will continue to review post-marketing data on RotaTeq as
that becomes available. Draft recommendations will be presented in
February, in preparation for a final recommendation and possible vote in
June.

**GSK's Human Rotavirus Vaccine Rotatrix**

Dr. Friedland said that GlaxoSmithKline had been developing this human
rotavirus vaccine since 1998. The goal has been to develop a safe and
effective vaccine for children worldwide designed to protect against
rotavirus infection, the leading cause of severe dehydrating diarrhea in
infants and children and the single greatest cause of diarrhea deaths in
children.

In 1999 the first licensed vaccine, Rotashield, was withdrawn from the
market after an association with intussusception, an uncommon but
intensely life-threatening event. Despite this setback, clinical
development of Rotarix continued, with the aim to license and distribute
it in developing countries where 90 percent of the 600,000 annual deaths
from rotavirus occur. Rotarix was first licensed in Latin America in
2004. Licensure in Africa, Asia, and Europe followed in 2005 through
2006. Licensure in Canada occurred earlier this month, and the U.S.
application was submitted in June.

The basis for preventing rotavirus gastroenteritis comes from studies of
natural disease. Velazquez and others have shown that rotavirus
infection induces immunity against subsequent infections of
gastroenteritis and that two infections confer virtually 100 percent
protection against moderate to severe disease, regardless of rotavirus
serotype. GSK chose to develop a human rotavirus vaccine in order to
mimic human infection, protect against moderate to severe disease,
prevent hospitalizations, reduce the socioeconomic burden caused by
rotavirus, and provide broad cross-reactive protective immunity. There
is a high degree of homology between human rotavirus proteins and human
rotavirus strains.

Rotarix vaccine is derived from a G1P(8) human rotavirus strain isolated
from a child in Cincinnati, Ohio. Cloning and culture passages resulted
in RIX4414, a live attenuated human rotavirus vaccine. RIX4414 and the
original unpassaged isolate genome differ by 12 nucleotide mutations,
encoding ten amino added substitutions. It is genetically stable from
seed to final vaccine.

Rotarix is a lyophilized vaccine, reconstituted with a liquid diluent
that contains calcium carbonate as a buffer. Each oral dose is 1
milliliter and contains at least 10^6^ cell-culture infected dose 50 of
live attenuated human rotavirus strain. It is administered in two oral
doses, the first beginning at six weeks of age, with an interval of at
least four weeks before the second dose. The two-dose series should be
completed by 24 weeks of age. A second-generation, ready-to-administer
liquid formulation is currently in development.

Rotarix is now licensed in over 100 countries and recommended in
national immunization programs worldwide. In February 2007, it was
awarded WHO prequalification, which sets the stage for U.N. agencies
such as PAHO and UNICEF to purchase and use Rotarix in mass-vaccination
programs. Vaccine efficacy has been demonstrated in both developed and
developing countries against severe rotavirus gastroenteritis, rotavirus
gastroenteritis hospitalizations, any severity of rotavirus
gastroenteritis, and gastroenteritis hospitalizations of any cause.

Dr. Friedland presented results from Rota-023, a Phase III efficacy and
safety study that began in 2003 in 11 countries in Latin America and
also in Finland. Over 63,000 infants were enrolled and vaccinated.
Results were published in the *New England Journal of Medicine* in 2006.

Infants 6 to 13 weeks of age were randomized 1-to-1 to receive Rotarix
or a placebo, and the second dose was given one to two months later.
Routine immunizations, with the exception of OPV, were co-administered
according to local recommendations. All 63,225 infants were followed for
30 to 90 days after receiving their second dose of study vaccine. This
cohort was followed for a median of 100 days after the first dose. A
subset only from the 11 Latin American countries was followed for one
year for a vaccine efficacy analysis, and infants from 10 of the 11
Latin American countries were followed through a second year of vaccine
efficacy analysis.

The primary study objective was to determine if two doses of Rotarix can
prevent severe rotavirus gastroenteritis caused by circulating rotavirus
strains, starting from two weeks after the second dose until the
children were approximately one year of age. Secondary objectives
included efficacy against G1 and non-G1 serotypes; intent-to-treat
efficacy; efficacy using a Vesikari scaling system, a widely used
scoring system that assesses severity of GE episodes according to
distribution of clinical features; and efficacy through two years after
vaccination.

Severe gastroenteritis was clinically defined as diarrhea, three or more
loose stools in 24 hours with or without vomiting, that required
hospitalization and/or rehydration therapy in a medical facility.
Rotavirus was detected by ELISA in stool samples. The type of rotavirus
was determined by reverse transcriptase PCR followed by reverse
hybridization assay. This methodology allowed discrimination between G1
vaccine virus and wild-type G1.

Rotarix was highly efficacious in Latin America. Through the first year
of life, vaccine efficacy was 85 percent against severe rotavirus
gastroenteritis, using both the clinical case definition and the
Vesikari scoring system. Vaccine efficacy was 85 percent against
rotavirus gastroenteritis hospitalizations and 40 percent against
all-cause severe gastroenteritis regardless of etiology. It was
sustained at similar rates through the second year after vaccination
against severe rotavirus gastroenteritis, rotavirus gastroenteritis
hospitalizations, and all-cause severe gastroenteritis.

Statistically significant vaccine efficacy was demonstrated for common
circulating rotavirus types: G1P(8), G3P(8), G4P(8), and G9P(8).
Protection against Type G2P(4) was also demonstrated, though not
statistically significant, with wide confidence intervals, given the
overall small number of G2P(4) cases.

The second Phase III efficacy study, Study 036, was conducted in six
countries throughout Europe. Infants 6 to 14 weeks of age were
randomized 2 to 1 to receive Rotarix or a placebo, and a second dose of
vaccine was given one to two months later. All infants received
concomitant vaccination with the DTaP-HepB-IPV/Hib combination vaccine,
and a subset received concomitant vaccination with PCV7 or with
meningococcal C conjugate vaccine. All 3,994 infants were followed
through the first rotavirus season after vaccination and again through
the second rotavirus season after vaccination.

The primary efficacy objective in Study 036 was to determine if two
doses of Rotarix can prevent any rotavirus gastroenteritis caused by
circulating rotavirus strains, starting from two weeks after Dose 2
until one year of age. Secondary objectives included efficacy against
severe cases of rotavirus gastroenteritis, Types G1 and non-G1
serotypes, rotavirus hospitalizations, medically attended rotavirus
gastroenteritis, intent-to-treat efficacy, and efficacy through two
years after vaccination.

Gastroenteritis was defined as diarrhea, greater than or equal to three
loose stools in 24 hours, with or without vomiting. Severity was
assigned using the Vesikari scale. A score greater than or equal to 11
was defined as severe gastroenteritis. This scoring system was also used
in the Rotashield efficacy studies.

Rotarix was highly efficacious in Europe. Through the first rotavirus
season after vaccination, vaccine efficacy was 87 percent against any
severity of rotavirus gastroenteritis and 96 percent against severe
rotavirus gastroenteritis. Rotarix was 100 percent effective in
preventing rotavirus gastroenteritis hospitalizations and 92 percent
effective in preventing rotavirus gastroenteritis that required medical
attention. Rotarix efficacy was 75 percent against all-cause
gastroenteritis hospitalizations, regardless of etiology. Vaccine
efficacy was sustained through two rotavirus seasons after vaccination
against any severity of rotavirus gastroenteritis, severe rotavirus
gastroenteritis, rotavirus gastroenteritis hospitalizations, medically
attended rotavirus gastroenteritis, and all-cause GE hospitalizations.

In this study, 82 percent of the infants received their first dose of
study vaccine prior to the rotavirus season. As a result, six rotavirus
cases occurred prior to the time infants received their second dose of
study vaccine. Vaccine efficacy from Dose 1 up until the time the
infants received Dose 2 was able to be analyzed. Vaccine efficacy from
Dose 1 up to before Dose 2 against any severity and against severe
rotavirus gastroenteritis was 90 percent and 100 percent respectively,
with wide confidence intervals, given the small number of cases.

Statistically significant vaccine efficacy was demonstrated through two
rotavirus seasons for all circulating rotavirus types. It was 96 percent
against G1P(8) rotavirus, 86 percent against G2P(4) rotavirus, 94
percent against G3P(8) rotavirus, 95 percent against G4P(8) rotavirus,
and 85 percent against G9P(8) rotavirus.

Study 023 in Latin America was specifically designed and powered to
evaluate the risk of intussusception following administration of Rotarix
as compared to placebo. The primary endpoint for safety was a case of
intussusception diagnosed within 31 days of receiving the first or the
second dose of vaccine. Intussusception cases were detected by
independent, complementary methods. All hospitals in study areas were
informed about the study, and relevant departments at hospitals were
advised to contact study personnel regarding each case of
intussusception evaluated. Parents of participating infants were
informed about symptoms consistent with intussusception and instructed
to seek medical advice at the nearest hospital if symptoms indicative of
intussusception appeared and to also inform their investigator.

All potential intussusception cases were reviewed by an independent
clinical events committee, composed of a pediatric gastroenterologist, a
surgeon, and a radiologist, who remained blinded to treatment
allocation. They characterized cases as either definitive, probable, or
possible using Brighton criteria. In addition, safety was monitored by
an IDMC, which had the authority to unblind.

The primary safety objective in this study would be met if the upper
limit of the two-sided 95 percent confidence interval of the risk
difference for intussusception within 31 days after vaccination was
below 6 per 10,000. No statistically significant increase in incidence
of intussusception within 31 days after vaccination was defined as the
lower limit of the 95 percent confidence interval of the risk difference
being below zero.

With an incidence rate of three to five cases of definite
intussusception per 10,000 infants within 31 days in the placebo group,
the sample size in this study had more than 86 percent power to meet the
primary objective if the risk difference was truly zero. Each group,
Rotarix and placebo, had 31,000 infants. Within 31 days of any dose,
there were six cases of intussusception in the Rotarix group and seven
cases in the placebo group, with a relative risk of 0.85. Within the
safety surveillance period, which was a median of 100 days after Dose 1,
there were nine cases of intussusception in the Rotarix group and 16
cases in the placebo group, with a relative risk of 0.56. The results
indicate that Rotarix is not associated with an increased risk of
intussusception.

Of the 13 definite intussusception cases diagnosed within 31 days after
any doses, six occurred in the Rotarix group and seven in the placebo
group. The relative risk for a case of intussusception within 31 days of
any dose was 0.85, and the risk difference was negative 0.32. There was
no temporal clustering of cases after either dose.

A secondary safety objective in Study 023 was all serious adverse events
that occurred during the safety surveillance period. Significantly fewer
numbers of SAEs and hospitalizations occurred in the Rotarix group
compared to the placebo group. This was primarily driven by fewer
serious adverse events and hospitalizations related to vomiting and
diarrhea in the Rotarix group. A *post-hoc* analysis showed a 42 percent
reduction in the Rotarix group in hospitalizations for gastroenteritis
due to any cause.

An integrated summary of safety from all the randomized
placebo-controlled clinical trials was submitted with the U.S. licensing
application. The main integrated safety summary compares Rotarix at
potency greater than or equal to 10^6^ CCID 50, the potency intended for
use in the U.S. The integrated summary of safety includes data on
solicited adverse events, unsolicited adverse events, and serious
adverse events. Relative risk, accounting for study effect with a 95
percent confidence interval of Rotarix compared to placebo, was
estimated for each safety endpoint. Potential imbalances were defined as
the 95 percent confidence interval for the relative risk across studies,
excluding 1.0.

Looking at any intensity of solicited symptoms within eight days after
each of the two vaccinations, the integrated summary of safety shows
that similar percentages of infants in the Rotarix group and the placebo
group reported any intensity of fever, cough or runny nose, diarrhea,
vomiting, irritability and fussiness, or loss of appetite. Overall,
reporting rates of Grade 3 or severe intensity solicited symptoms in all
groups was low, mostly below 5 percent. In the eight-day period after
each of the two vaccinations, similar percentages of infants in the
Rotarix group and the placebo group reported Grade 3 fever, cough or
runny nose, diarrhea, vomiting, irritability and fussiness, or loss of
appetite.

At least one serious adverse event within the 31-day postvaccination
period was reported by 1.7 percent of the infants who received Rotarix
and by 1.9 percent of those who received placebo. Diarrhea,
gastroenteritis, and dehydration were reported by more infants in the
placebo group than in the Rotarix group, as noted by the 95 percent
confidence interval for the relative risk, excluding 1.0. All other
serious adverse events reported within the 31-day postvaccination
period, including deaths, intussusception, bronchiolitis, pneumonia, or
nervous system disorders, were reported by similar proportions of
subjects in both groups, as indicated by the 95 percent confidence
interval for the relative risk, overlapping 1.0.

All but one of the fatalities were reported in Study 023, conducted in
Latin America. There was an imbalance of deaths related to pneumonia. An
analysis of serious adverse events of events medically related to
pneumonia and of hospitalizations linked to pneumonia did not confirm
the imbalance in the number of cases of fatal pneumonia in Study 023.
The overall SAE profile shows that Rotarix, compared to placebo, is
associated with fewer serious adverse events associated with
gastroenteritis disease.

Rotarix is a live attenuated human rotavirus vaccine that replicates
well in the GI tract. Viral shedding following Rotarix administration
was evaluated by the presence in stool of rotavirus antigen detected by
ELISA and the presence of live rotavirus particles in stool detected by
a titration assay. The rotavirus antigen shedding as assessed by ELISA
was studied in a subset of all subjects in 7 of the 11 studies submitted
in the U.S. licensing application. Rotavirus antigen shedding was
predominantly observed on Day 7 after Dose 1 and decreased thereafter.

Data on live virus shedding in the clinical trials are limited. In two
studies, all stool samples collected at Day 7 after the first vaccine
dose were tested by ELISA for rotavirus antigen; the remaining samples
were tested for the presence of live rotavirus in cell culture by
indirect fluorescence. In Thailand, 56 percent of infants were shedding
antigen after Dose 1 and 46 percent of the antigen shedders tested
positive for live rotavirus. In Finland, 58 percent of infants were
shedding antigen after Dose 1 and 46 percent of those tested positive
for live rotavirus. The percentage of vaccinees with live rotavirus
detected in stool was estimated by multiplying the proportion of stools
that were rotavirus antigen positive by the proportion of rotavirus
antigen positive stools that contained live rotavirus. Thus, it was
estimated that approximately 26 percent of the infants were shedding
live rotavirus at Day 7 after Dose 1 in these two studies.

Rotarix has been investigated in the U.S. when co-administered with the
routine vaccinations Pediarix, Prevnar, and ActHIB. The objective of the
study was to demonstrate that co-administration with Rotarix does not
impair the immune response to any of the antigens contained in each of
the routine infant vaccinations currently included in the ACIP infant
vaccination schedule.

A similar percentage of infants in the co-administered and the
separately administered groups achieved seroprotective antibody
concentrations to PRP; hepatitis B surface antigen; poliovirus Types 1,
2, 3; and diphtheria and tetanus. Geometric mean concentrations of
antibodies to pertussis antigens PT, FHA, and PRN were similar in the
co-administered and separately administered groups, and geometric mean
antibody concentrations of pneumococcal antibodies were similar in the
two groups.

All 17 predefined non-inferiority criteria for comparisons between the
co-administered and the separately administered group were met. The
conclusion from this study is that Rotarix does not negatively impact
the immune response to the antigens present in Pediarix, ActHIB, or
Prevnar.

In July 2007, approximately 12 million doses of vaccine were
distributed. As of the 11th of July, 140 spontaneous reports of
intussusception after Rotarix vaccination had been received by GSK, 88
of which had sufficient information to allow classification as definite
intussusception according to Brighton case definition; of those, 56 were
reported to occur within 31 days after Rotarix vaccination. GSK
estimates that 556 cases of intussusception within 31 days of Rotarix
vaccination would have been expected to occur, based on expected
incident rates of intussusception in infants by region, the proportion
of intussusception expected to occur each month by age in the first year
of life, and the number of doses distributed. While the number of doses
distributed does not necessarily equal the number of doses administered
and recognizing that there is unknown surveillance quality in many
countries, the post-marketing experience to date shows no indication of
increased intussusception risk.

Ongoing pharmaco-vigilance and risk-management activities include
surveillance for intussusception cases reported in post-licensure
settings and safety studies conducted in settings of universal
vaccination, designed and powered to investigate the incidence of
intussusception post-rotavirus vaccination. One is a post-authorization
safety study being conducted in Mexico, which has a national rotavirus
immunization program. This study, involving the IMSS network throughout
Mexico, includes 224 pediatric health facilities with an annual birth
cohort of 575,000. GSK will be monitoring for drifts and shifts in
vaccine strain after market introduction. Studies are currently being
conducted to assess horizontal transmission of vaccine virus strain
between twins, immunogenicity and safety in preterm infants,
immunogenicity and safety in HIV-positive infants, and vaccine
effectiveness.

In summary, the clinical database is sufficiently large to evaluate the
safety of this vaccine. There has been no increased risk of
intussusception among infants vaccinated with Rotarix compared to
placebo, and the reactogenicity and safety profile of Rotarix is
clinically acceptable and similar to placebo. Rotavirus antigen shedding
occurs in about 50 percent of subjects, with peak excretion about the
seventh day after the first dose. Live virus shedding occurs in about 26
percent of infants at seven days in two clinical trials, and Rotarix
does not negatively impact the immune response to the antigens present
in Pediarix, Prevnar, and ActHIB. Rotarix prevents rotavirus
gastroenteritis, as demonstrated in the Phase III study in Latin America
and the Phase III study in Europe; in Europe, protection against any
severity of rotavirus gastroenteritis was 87 percent, and severe disease
was 96 percent. Rotarix prevents rotavirus gastroenteritis caused by
strains G1, G2, G3, G4, and G9, and efficacy persists through two years
after vaccination.

**Discussion**

Dr. Hull asked if there had been any surveillance for clinical illness
or infection in diaper changers. Dr. Friedland replied this had not been
done, but that rates of vomiting and diarrhea and other
gastroenteritis-like symptoms are comparable in placebo and those
receiving the vaccine.

Ms. Stinchfield asked what the time frame was on the preemie studies and
the HIV studies. Dr. Friedland replied that results for the premature
infant study were expected in the third quarter of 2008 and for
horizontal transmission, results were expected in the second quarter of
2008. For immunocompromised infants, results are also expected in the
second quarter of 2008.

Dr. Katz asked about the range of titers of the shed virus. Dr.
Friedland said the data were limited, but in the clinical studies where
this was tested, of those who came down with wild-type rotavirus
disease, 68.6 percent were shedding live rotavirus in their stool. The
quantification, expressed as FFU per 200 milligrams per stool, was
threefold higher in those who had live rotavirus wild-type disease
compared to those who shed vaccine virus.

Ms. Johammer from the California Department of Public Health
Immunization Program asked if the vaccine had to be mixed and how
complicated that was for storage and other issues. Dr. Friedland
responded that the current presentation is a lyophilized vaccine, and
the process to prepare it is no different than any other currently
marketed lyophilized vaccine. GSK is planning to bring forth a liquid
formulation (development plans are under review by the FDA) and has
conducted four clinical studies with a liquid formulation, with a large
amount of CMC data, to demonstrate that the vaccine is as immunogenic
and safe with the liquid formulation.

Dr. Slade asked whether any cases of Kawasaki\'s were observed. Dr.
Friedland replied that there were no reports of Kawasaki disease in the
post-marketing experience.

In the completed and ongoing clinical trials, observed rates of Kawasaki
disease were on par with what would be expected.

**PRV (RotaTeq) Update**

[Coverage and Adherence with Age Recommendations]{.underline}

Dr. Cortese reminded the committee that ACIP recommended the pentavalent
rotavirus vaccine, RotaTeq, in February of 2006 for all infants, in a
three-dose series to be given at ages two, four, and six months. The age
recommendations were those studied in the large safety and efficacy
trial. Vaccination should not be initiated after 12 weeks of age because
of insufficient data on safety in administering the first dose to older
infants. Subsequent doses are to be given four to ten weeks apart, and
no doses are to be given after age 32 weeks.

To assess vaccine uptake and adherence to these recommendations for
doses administered as of approximately May 31st, 2007, three information
sources were used. The Sentinel Area Immunization Information System
covers six areas in the United States and meets certain criteria, such
as covering 10,000 children or more aged less than six years. They have
approximately 90 percent provider sites participating in the registries
and incorporate procedures to increase completeness and accuracy. The
Vaccine Safety Datalink is a collaborative project involving CDC and
several large HMOs. Data were also received from state immunization
registries. Since these cover entire states, they have variable levels
of provider participation and completeness.

In 36 states and the District of Columbia, 1.6 million doses were
reported to have been administered through May 2007, approximately
one-quarter of the 6.2 million doses reported distributed by the
manufacturer through that time. Sentinel site registries provide
coverage estimates for specific age groups. The number of
three-month-olds in the registries ranges from 200-500 in 4 sites to
7,000 in Michigan. One-dose rotavirus vaccine coverage in these sites
increased from 20 to 30 percent at the end of 2006 to 40 to 60 percent
in May 2007.

Using data from the sentinel registries, Dose 1 coverage with rotavirus
vaccine among three-month-olds in May 2007 was compared with Dose 1
coverage of DTaP and PCV7. Rotavirus vaccine coverage ranged from 40 to
64 percent, for an average of 49 percent, compared with an average of 86
percent for one dose of the other vaccines. This is considered a
respectable uptake for a new vaccine.

There are likely some real or perceived barriers, as with any new
vaccine, such as reimbursement issues. The tight age frame for starting
the series could also affect coverage. A recent provider survey explores
these issues, and results should be presented in February. To assess how
well providers are adhering to age recommendations, the study focused on
administration of Dose 1. IAS sentinel sites showed that 86% of Dose 1
was given between ages 6-12 weeks and VSD showed 93 percent. Small peaks
occur at approximately four and six months of age.

A study limitation is that the date of vaccination is used to determine
the dose number, so the first date of vaccine administration is
automatically counted as Dose 1. It is possible that some of this late
peak is actually second or third doses being administered to infants
whose previous doses were not counted in the registry. This could be an
even greater limitation in state registries, since they have less
complete provider participation. Using sentinel sites, the study looked
at infants who received three doses of vaccine, to be more confident
that first doses were actually first doses. Here 95 percent of the first
doses were given at 6 to 12 weeks with very small peaks at those later
ages. In all three data sources, only 0.2 percent or less of doses were
recorded as being given before six weeks; 2 percent or less were given
after age 32 weeks.

In summary, coverage with one dose of rotavirus vaccine among
three-month-olds in sentinel site areas reached approximately 50 percent
by May 2007, and the data suggest that providers' adherence to the ACIP
age recommendations is high.

[Safety Monitoring Update]{.underline}

Dr. Haber talked about intussusception reports to VAERS since licensure
in March 2006. From March 2006 until August 2007, about 9.1 million
doses of RotaTeq were distributed. During that time period, 160
intussusception reports were confirmed based on Brighton collaboration
case definition Level 1. Of these, 47 were within 1 to 21 days after
vaccination and 27 of the 47 reports were within one to seven days.
There is a peak in Week 1 compared to Week 2 and 3, with another peak at
Weeks 4 and 5 and 6. For Dose 1 there were 50 reports, with 68 reports
for Dose 2 and 42 reports for Dose 3.

In comparing the observed number of reports with what would be expected
by chance alone, age stratified analysis is important since the baseline
of intussusception rate varies tenfold during the first six months of
life and during this time three doses are administered. There are also
two important data assumptions: reporting completeness to VAERS and the
number of doses administered.

Looking at the observed versus the expected within 1 to 21 days after
any dose, for all the three age groups, the cases observed in VAERS are
lower than expected by chance alone. The rate ratio is 0.3 and the
confidence interval does not include 1. This assumed 100 percent
reporting and 100 percent of doses distributed. Looking at one to seven
days for any dose, stratified by age group, again the reports to VAERS
are lower than expected. The rate ratio is 0.51, the confidence interval
does not include 1, and 100 percent is assumed for reporting and
administration.

The sensitivity analysis is closer to what is assumed to be reality: 75
percent reporting and 75 percent doses distributed. At 1 to 21 days,
there were 62 cases in VAERS, whereas 113 would be expected by chance
alone, and at one to seven days, there were 36 cases, with 38 expected.
The rate ratio still does not include 1. Calculations were also done for
the 50 percent assumptions, even though that is an unlikely scenario.
The VAERS cases were higher than expected by chance alone and the rate
ratio increased by 1 and 2 for the two onset intervals.

The Vaccine Safety Datalink from May 21 to October 6, 2006 has a total
of 111,521 vaccinations. Three cases of IS were identified based on ICD9
code within 30 days of vaccination. Chart review to confirm the cases is
currently under way - one case after Dose 1 with an onset interval of 20
days, and two cases after Dose 2, with onset intervals of 17 and 10
days. There would be 3.4 reports of intussusception expected by chance
alone. The data are based on VSD Rapid Cycle Analysis background rates.
Uptake at six VSD Rapid Cycle sites was about 43 percent in Dose 1, and
33 and 22 percent in Doses 2 and 3, respectively.

In conclusion, the observed intussusception rates following RotaTeq are
no greater than expected. Data from VAERS should be interpreted as being
from passive surveillance. VSD data after over 100,000 vaccinations saw
no evidence of increased risk. The company continues to follow the VSD
and Merck post-licensure cohort studies.

**Discussion**

Dr. Morse asked when the committee might see an evaluation of reduction
in disease burden. Dr. Cortese replied that systems had already been set
up to look at both burden and vaccine effectiveness. Dr. Parashar added
that these included the NVSN active surveillance platform, an evaluation
linking hospitalization data with immunization registries of Texas
children, perhaps an evaluation with New York State through EIP sites,
and using the Vaccine Safety Datalink to look at the disease impact in
addition to monitoring safety. It is hoped that the data will be ready
for presentation in summer or fall of 2008.

Dr. Neuzil asked whether the coverage for children getting PCV and DTap
would be the highest percentage that could be reached for rotavirus, if
the 3-month age restriction is followed. She thought the numbers seemed
very low and wondered if they reflected incomplete reporting to the
registries. Dr. Cortese reminded her that the data presented were for
infants aged 3 months. The Montana sentinel site did have a low
estimate. Nationally about 88 to 90 percent of infants had one dose of
DTaP by age 3 months (NIS data, infants born 2002-4).

Dr. Morse asked if there were any reports of variability in coverage of
vaccine by state for the underinsured. Dr. Cortese responded that there
were no specific data by state and insurance data from the sentinel
registries were incomplete. Dr. Schuchat added that the annual ongoing
National Immunization Survey of 19- to 35-month-olds now has an annual
module about individual insurance as well as the state and location, and
coverage will be tracked by particular vaccines and by individual and
state insurance status.

Dr. Katz asked if Merck or GSK had any studies in sub-Saharan Africa or
southeast Asia. Dr. Friedland responded that there were ongoing efficacy
studies currently in South Africa and in southeast Asia. Dr. Goveia
reported that Merck has active studies looking at efficacy, safety, and
immunogenicity in sub-Sahara Africa and southeast Asia, in partnership
with PATH, and a robust demonstration project ongoing in Nicaragua.

Dr. Neuzil wondered what the best baseline would be for reporting
intussusception to VAERS and the number of vaccines distributed, as well
as the best baseline for the sensitivity analysis, because clearly it is
not 100 percent. Dr. Iskander responded that the committee may want to
think in terms of modeling rather than sensitivity analysis. A lot of
inferential data indicate reporting is actually pretty high, but unless
and until there is a national immunization registry, there is no direct
way to measure coverage or underreporting. The 75/75 figure seems to be
the consensus.

Dr. Parashar noted that if one knew the rate of completeness and
proportion of doses distributed that were given, there could be more
specificity about the level of risk. Those numbers are likely change
over time and reporting fluctuates depending on publicity, the media and
events. It is very hard to determine the best assumptions for those two
parameters. The VSD is the gold standard, with good-quality data,
through a cohort analysis and about 111,000 vaccinations.

Dr. Verstraeten from GlaxoSmithKline suggested thaat without national
coverage figures, one could use existing numbers to estimate the actual
amount of doses distributed and administered. Dr. Iskander responded
that this would mean sub-modeling within one of the already modeled
variables and no one wants that.

**Update of Hepatitis B**

**Dr. Cindy Weinbaum, CDC/NCHHSTP/DVH**

**Hepatitis B Vaccination of Adults**

Dr. Weinbaum explained that in 1991 the ACIP and other professional
medical organizations endorsed a national strategy with four main
components: screening pregnant women and immunizing infants of infected
mothers to prevent perinatal transmission; universal vaccination of
infants to prevent infections during childhood and at later ages;
catch-up vaccination of children and adolescents not vaccinated
previously; and vaccination of adolescents and adults in groups at
increased risk for infection. The incidence of acute hepatitis B has
declined overall by 78% from the 1991 recommendations through 2006, most
dramatically in children. Even in adults ages 25-44 years, in which
incidence is highest, there has been a 75 percent decline.

There is still room for improvement in preventing disease among adults,
including prior opportunities for vaccination among patients who are
diagnosed with acute hepatitis B. In a sentinel county study between
2001 and 2004, 61 percent of individuals with reported acute hepatitis B
had previously had an opportunity for immunization, through
incarceration, STD treatment, or drug treatment. A survey of states
found that 9.5 million people were seen annually in STD clinics, HIV
counseling and testing sites, substance abuse and correctional settings,
which represents only about 7 percent of people between the ages of 18
and 45.

In October of 2005, the ACIP approved updated hepatitis B vaccination
recommendations for adults, which were published in the *MMWR* in
December 2006. Hepatitis B vaccine for all unvaccinated adults at risk
had been a standing recommendation since the vaccine was first approved.
In the new recommendations, it was also recommended for all adults
seeking protection, without acknowledgment of a specific risk factor.

Practice-based vaccination strategies were offered in settings with
access to a high proportion of at-risk adults, including STD and HIV
testing and treatment facilities, substance abuse treatment facilities,
correctional facilities, healthcare providers who serve injection-drug
users or men who have sex with men, hemodialysis centers, and adult
institutions for the developmentally disabled. CDC encouraged states to
use Section 317 funds to purchase adult hepatitis B vaccine, stressing
the need to hasten elimination of HBV transmission and implement ACIP
recommendations. States were encouraged to convene managers from
cooperating STD/HIV immunization and hepatitis programs to determine
vaccine resources, target populations, potential venues for vaccination,
numbers of doses needed, and roles of the participating programs and to
develop an implementation and evaluation strategy.

More recently, about \$20 million in Section 317 immunization funds were
made available to purchase hepatitis B-containing vaccines for programs
that serve adults at risk for viral hepatitis. These funds represented a
one-time savings during the transition to a centralized vaccine
distribution system, and were distributed to 51 project areas.
Evaluation is planned to assure that these doses were distributed and
administered in the venues recommended.

CDC has also been working with additional organizational partners,
including the National Association of State and Territorial AIDS
Directors, the National Council of STD Directors, and the National
Association of City and County Health Officials, in addition to the
Association of Immunization Managers. The adult hepatitis coordinators,
immunization program managers, and HIV and STD program managers have all
been working together, and CDC is developing cross-cutting strategic
plans for its divisions to work together at the central level as well.
After the updated recommendations were published, CDC offered Web-based
education and training that focused on setting-based implementation
strategies.

In summary, progress has been made in eliminating HBV transmission since
1991. Hepatitis B incidence in adults has declined by over 70 percent,
but there is currently a time-limited opportunity to accelerate
elimination of HBV transmission by increasing vaccine coverage among
at-risk adults. The recent recommendations and additional funding are
expected to accelerate this progress.

**Discussion**

Dr. Morita commented that the 317 funding to purchase vaccine for this
initiative will make it much easier to achieve the Healthy People 2010
objective and suggested that the funding should be made available for
other adult vaccine initiatives. Dr. Lett added that the funding helps
with forming and strengthening partnerships.

**Identification and Public Management of Persons Chronically Infected
with Hepatitis B Virus**

Dr. Weinbaum explained that the CDC was in the process of developing
recommendations for the identification and public health management of
persons chronically infected with HBV. There are 1 million to 1.4
million persons in the U.S. who are hepatitis B surface-antigen (HBsAg)
positive. Hepatitis B is the underlying cause of some 2,000 to 5,000
deaths a year. In recent years, the epidemiology of prevalent hepatitis
B has changed in the U.S., and more prevalent disease is currently found
among people born in countries with high endemicity than people who
acquired the infection in this country. Identifying individuals who are
chronically infected with hepatitis B virus provides an opportunity for
the prevention of transmission by vaccination of contacts, as well as
for treating the infected individuals. With improving treatment options,
identifying infected persons increasingly provides opportunities to
improve the health of the public.

These recommendations are intended to complement NIH\'s consensus
development conference on the management of hepatitis B scheduled for
October, 2008. The many existing recommendations will be compiled into a
single document that will also recommend testing for additional
populations and outline components of a testing and public health
management program. Certain components of public health management
programs were outlined in the appendices of two ACIP recommendations in
2005 and 2006: educating patients in order to prevent transmission to
others and protect the infected individual\'s liver from further harm;
managing contacts in order to identify tests; vaccinating household,
sex, and needle-sharing contacts; referral for evaluation by physicians
experienced in management of chronic liver disease; and reporting to
health departments. A draft of the recommendations was reviewed by a
consultants meeting in February 2007; additional input is also being
sought so that they might be published in 2008.

Existing recommendations say that to prevent nosocomial transmission,
donors of blood, plasma, organs, tissue, and semen are mandated to be
tested. Hemodialysis patients are recommended for testing. To manage
exposures, pregnant women, infants born to surface-antigen-positive
women, contacts of surface-antigen-positive persons, and sources of
blood and body fluid exposures in the case needle sticks or sexual
assault are also recommended for testing.

Testing individuals with increased prevalence of infection has been
recommended before. To the previous recommendation to test foreign-born
persons from countries with a prevalence of 8 percent or higher, CDC is
proposing adding persons from countries of intermediate prevalence: 2 to
7 percent. It is also proposing adding recommendations for testing
injection-drug users and men who have sex with men, although for persons
with ongoing risk, the emphasis is still on vaccination. HIV-positive
persons are already recommended for testing. As a matter of medical
management, persons on immunosuppressive therapy or about to start
immunosuppressive therapy and persons with elevated ALTs and ASTs have
been added.

Challenges to implementing these recommendations are expected. Some will
be patient related, including lack of awareness of the need for testing
and returning to obtain test results or communicating with contacts.
Awareness of the need for testing will also need to be raised among
providers. Insurance reimbursement for testing needs to be investigated
and improved methods for risk ascertainment and contact tracing and
management will be necessary.

Regarding infrastructure, there is currently no specific funding for
counseling and testing for chronic hepatitis B or for follow-up of
HBsAg-positive persons in a public health setting. Health department
registries exist in many states for chronic hepatitis B, but there is
minimal federal support. The lack of availability of medical care for
HBsAg-positive persons who are newly identified will be a challenge,
along with point-of-care tests that enable people to receive their
results immediately.

In summary, these new recommendations are intended to compile existing
recommendations for testing in a single document, target new populations
for testing, and outline components of a testing program with some
guidance for implementation.

**Agency Updates**

**CDC**

Dr. Schuchat reported that a CDC working group had been developing
recommendations for post-exposure interventions to prevent HBV, HCV, or
HIV infection and tetanus for persons wounded during bombings and other
mass casualty events in the U.S. This group was led by the immunization
and injury staff, but included representatives from across CDC, as well
as from NACCHO, CSTE, and the Terrorism Injury, Information,
Dissemination, and Education Partnership. The guidance adapted the
existing recommendation specific to the mass-casualty setting and
represented a consensus judgment of U.S. public health authorities. It
also benefited from the experience of the U.K. and Israel. The guidance
is undergoing CDC clearance, and a prepublication copy will be provided
to ACIP members, although they are not expected to vote on it.

**CMS**

Ms. Murphy of CMS added to the above that the immunization program has
completed the VFC revision of their operations guide, which is now on
the Web site, so there will be more emphasis on quality and on
collaboration between CMS and CDC in fraud and abuse. Three more states
have revised their VFC administration rates and one of those has
actually gone to the max.

**DOD**

Colonel Cieslak had no new information to present, although there are
many current vaccine issues that interest the military, starting with
anthrax and both the licensed and some new generation anthrax vaccines.
ACIP has constituted an anthrax working group, as well as one for the
Japanese encephalitis new generation vaccine. The military continues to
immunize against smallpox. Well over a million doses have been given and
about one case of contact vaccinia or transfer vaccinia per month
continues to be seen on average. Most have been trivial, but monitoring
continues, albeit passive reporting.

The DoD is in late-stage trials with a new bivalent adenovirus Type 4/7
vaccine, since there has been some significant adenovirus Type 14
disease in the military as well as in some civilian locales, such as
Oregon. There is interest in cross-protection and whether more serotypes
need to be added.

Dr. Hachey added that the DoD had started its seasonal influenza
program. It continues to have a policy of universal influenza
immunization for everyone in uniform, with both live attenuated and
inactivated vaccine.

**HRSA**

Dr. Evans said that an update on the autism hearings had been put on the
Court\'s Web site. The Court held a major hearing last June on the first
of three theories that are going to be pursued. The first theory was the
combined hypothesis of MMR vaccine-caused autism as well as
mercury-caused autism. A combined theory was what the petitioners chose
to do first, and that lasted almost three weeks. At petitioners\'
request, the Court has adopted a test cases approach with three claims,
families, and children for each theory. The first hearing involved the
Cidello family, and two other test cases are being held. Decisions will
be rendered in approximately six months.

The second major hearing for the thimerosal theory will be held with
three test cases during the last three weeks of May, and the decision
will not be for another six months after that. The third theory and
hearings are not yet clear, but the final decisions, starting with the
special masters and the appeals that follow probably will not be in much
before 2011. Only when it reaches the level of the Federal Circuit Court
of Appeals are precedents set and that would be final unless appealed to
the Supreme Court. The Court made available the entire transcript for
the June hearing, as well as audio files for each of the witnesses that
testified.

**NVPO**

Dr. Strikas reported that the National Vaccine Advisory Committee had
just met on October 23rd and 24th. Highlights included a discussion
about trying to develop and enhance NVAC recommendation for improvement
in vaccine coverage among adults. There was an update on revising the
national vaccine plan, which was last written in 1994. The Institute of
Medicine will convene an expert committee to review priorities and a
series of meetings with stakeholders beginning in January 2008. The ACIP
will be informed and invited to participate in that process.

There was a discussion at the NVAC meeting about influenza vaccine
prioritization in a pandemic, and there will be a process with ACIP and
NVAC to review that information. The NVAC adopted a draft report on
mandates for adolescent vaccination. There was a report from the
committee\'s financing working group about financing pediatric vaccines,
as well as plans for stakeholders meetings in January to review their
white paper on this topic. The vaccine safety subcommittee is completing
an inventory of vaccine-safety activities across the government.
Finally, the NVAC had earlier recommended that NVPO host a meeting of
stakeholders on immunization information systems or registries, to
develop recommendations on how provider participation can be improved
and systems can be better funded. That meeting will occur in February
2008 in Washington.

**Public Comment**

Dr. Williamson, a hematologist and oncologist practicing in Muncie,
Indiana, spoke on behalf of his son Philip, who is now five years old.
At about one year of age, he had various thimerosal-containing vaccines
and also other heavy immunogenic load, which his father was convinced
caused a precipitous decline in his development. He had difficulty with
chronic diarrhea, screaming, and extreme sound sensitivity.

Assuming that the incidence of autism, 1 to 166 currently, is going to
increase, Dr. Williamson said he had an alternative strategy that the
committee perhaps might consider. Based on Internet research regarding
his son's symptoms, he discovered PDD and parent groups whose children
had similar symptoms. One parent suggested trying a gluten-free and
casein-free diet. When this diet was implemented, Philip almost
immediately began using words and phrases, something he had not done for
a year and a half. During week two, despite continued speech
improvement, he developed florid sweats, redness and agitation, similar
to drug withdrawal. Dr. Williamson learned that gluten and casein do
transform into gluteomorphin and caseomorphin; research from 1996 shows
the guts of children can abnormally absorb mannitol and lactulose and
could go to the brain, thereby causing a cyclical drug effect. By
removing that, he felt his son was going through withdrawal, sleeping
multiple hours a day.

As a medically trained physician, Dr. Williamson felt he was straddling
two worlds, but they continued with various other treatments regarding
diet, antifungals, antibiotics, supplements and vitamins. The son has
also been receiving chelation therapy, and he is now fully able to
express himself, is mainstreamed in school, playing with his peers, and
doing normal activities.

He implored the committee to consider alternative strategies, similar to
screening for autoimmune diseases and PKU, and called for a rigorous,
long-term prospective study of children who do receive the vaccines, and
consider removal of thimerosal and other unnecessary preservatives. Most
children and adults have normal levels of glutathione to help detoxify,
but some do not have the ability to get rid of the metals and other
toxins. This is an opportunity to build partnerships with physicians and
parents and fulfill the motto of CDC for safer, healthier people.

Mr. Scott Lassiter with Safe Minds said he had spoken at the June ACIP
meeting of the need to analyze thimerosal risks and referred to the
expert NIH panel report to Congress that said CDC studies on thimerosal
were seriously flawed. Contrary to CDC press releases, there has been no
interruption in thimerosal this decade. In fact the committee began
encouraging thimerosal-based flu vaccine for pregnant women in 2001,
causing the rate of vaccination in that group to increase from 7 to 30
percent, which means almost one-third of recent newborns are receiving
mercury in utero. There is no established toxicity limit for thimerosal
and there has never been a thimerosal group versus a no-thimerosal group
study. He urged committee members to reach out to experts outside of CDC
and to contact Safe Minds or other autism organizations. This committee,
in his opinion, was far overdue in stating a preference for mercury-free
vaccines.

Ms. Beauvais said that parents were the consumers of vaccines and the
ones who had to deal with the imposed mandates. As the mother of four
children, she was a staunch proponent of vaccines, but was asking ACIP
to state a preference for thimerosal-free vaccines. All four of her
children were screened for HG toxicity with a developmental doctor and
one has autism. The family has spent hundreds of thousands of dollars
restoring their children, whom she believes do not have the ability to
detox thimerosal. She was not informed or given the choice of
thimerosal-free vaccines. Her autistic daughter has been found to have a
mercury toxicity equivalent to somebody who works in the mining
industry. She has to be IV-chelated every month and health insurance
doesn\'t cover it. She urged the ACIP to take the moral high ground and
take the thimerosal out of the vaccines.

[As there was no further public comment, the meeting was
adjourned.]{.mark}

> I hereby certify that to the best of my knowledge, the foregoing
> Minutes of the October 24-25, 2007 ACIP Meeting are accurate and
> complete.

December 17, 2007

Dale Morse, M.D., M.S.

Chair, Advisory Committee on Immunization Practices

**[PARTICIPANTS]{.mark}**

[]{.mark}

[[CHAIR]{.underline}]{.mark}

[DALE L. MORSE, M.D.]{.mark}

[Director, Office of Science and Public Health]{.mark}

[New York State Department of Health]{.mark}

[Albany, New York]{.mark}

[]{.mark}

[[EXECUTIVE SECRETARY]{.underline}]{.mark}

[LARRY K. PICKERING, M.D.]{.mark}

[Senior Advisor to the Director]{.mark}

[NCIRD]{.mark}

[Centers for Disease Control and Prevention]{.mark}

[Atlanta, Georgia]{.mark}

[]{.mark}

[]{.mark}

**[MEMBERS]{.mark}**

[]{.mark}

[CAROL BAKER, M.D.]{.mark}

[Professor of Pediatrics]{.mark}

[Molecular Virology and Microbiology]{.mark}

[Baylor College of Medicine]{.mark}

[Houston, Texas]{.mark}

[]{.mark}

[ROBERT L. BECK, J.D.]{.mark}

[Consumer Representative]{.mark}

[Palmyra, Virginia]{.mark}

[]{.mark}

[LANCE CHILTON, M.D.]{.mark}

[General Pediatrics and Adolescent Medicine]{.mark}

[University of New Mexico School of Medicine]{.mark}

[Alburquerque, New Mexico]{.mark}

[]{.mark}

[PAUL CIESLAK, M.D.]{.mark}

[Medical Director, Immunization Program]{.mark}

[Oregon Public Health Division]{.mark}

[Portland, Oregon]{.mark}

[]{.mark}

[ALLEN CRAIG, M.D.]{.mark}

[State Epidemiologist]{.mark}

[Tennessee Department of Health]{.mark}

[Nashville, Tennessee]{.mark}

[JANET ENGLUND, M.D.]{.mark}

[Associate Professor]{.mark}

[University of Washington]{.mark}

[Seattle, Washington]{.mark}

[]{.mark}

[HARRY HULL, M.D.]{.mark}

[State Epidemiologist and Director]{.mark}

[Minnesota Department of Health]{.mark}

[Minneapolis, Minnesota]{.mark}

[]{.mark}

[FRANKLYN JUDSON, M.D.]{.mark}

[Professor, Departments of Medicine and Preventive Medicine]{.mark}

[University of Colorado at Denver]{.mark}

[Denver, Colorado]{.mark}

[]{.mark}

[SUSAN LETT, M.D., M.P.H.]{.mark}

[Medical Director]{.mark}

[Massachusetts Department of Public Health]{.mark}

[Jamaica Plain, Massachusetts]{.mark}

[]{.mark}

[TRACY LIEU, M.D.]{.mark}

[Associate Professor of Ambulatory Care and Prevention]{.mark}

[Harvard Pilgrim Healthcare and Harvard Medical School]{.mark}

[Boston, Massachusetts]{.mark}

[]{.mark}

[JULIE MORITA, M.D.]{.mark}

[Medical Director, Immunization Program]{.mark}

[Chicago Department of Health]{.mark}

[Chicago, Illinois]{.mark}

[]{.mark}

[KATHLEEN NEUZIL, M.D., M.P.H.]{.mark}

[Clinical Associate Professor of Medicine]{.mark}

[University of Washington]{.mark}

[Seattle, Washington]{.mark}

[]{.mark}

[PATRICIA STINCHFIELD, NP]{.mark}

[Director, Pediatric Infectious Disease and Immunology]{.mark}

[Children\'s Hospitals and Clinics of Minnesota]{.mark}

[St. Paul, Minnesota]{.mark}

[]{.mark}

[CIRO VINCENT SUMAYA, M.D., M.P.H.]{.mark}

[School of Rural Public Health]{.mark}

[Texas A&M University System Health Science Center]{.mark}

[College Station, Texas]{.mark}

[]{.mark}

[]{.mark}

**[EX-OFFICIO MEMBERS]{.mark}**

[]{.mark}

[JAMES E. CHEEK, M.D.]{.mark}

[National Epidemiology Program]{.mark}

[Indian Health Program]{.mark}

[Alburquerque, New Mexico]{.mark}

[]{.mark}

[TED CIESLAK, M.D.]{.mark}

[Department of Defense]{.mark}

[Falls Church, Virginia]{.mark}

[]{.mark}

[CAROLYN DEAL, M.D.]{.mark}

[National Institutes of Health]{.mark}

[Bethesda, Maryland]{.mark}

[]{.mark}

[GEOFFREY EVANS, M.D.]{.mark}

[Director, National Vaccine Injury Compensation Bureau]{.mark}

[Rockville, Maryland]{.mark}

[]{.mark}

[BRUCE GELLIN, M.D.]{.mark}

[Director]{.mark}

[National Vaccine Program Office]{.mark}

[Washington, D.C.]{.mark}

[]{.mark}

[WAYNE HACHEY, DO, M.P.H.]{.mark}

[Director, Preventive Medicine and Surveillance]{.mark}

[Office of the Assistant Secretary of Defense]{.mark}

[Falls Church, Virginia]{.mark}

[]{.mark}

[FLORENCE HOUN, M.D.]{.mark}

[Food and Drug Administration]{.mark}

[Rockville, Maryland]{.mark}

[LINDA MURPHY]{.mark}

[Senior Health Insurance Specialist]{.mark}

[Centers for Medicare and Medicaid Services]{.mark}

[Baltimore, Maryland]{.mark}

[]{.mark}

[KRISTIN NICHOL, M.D.]{.mark}

[Chief of Medicine]{.mark}

[VA Medical Center]{.mark}

[Minneapolis, Minnesota]{.mark}

[]{.mark}

[]{.mark}

**[LIAISON REPRESENTATIVES]{.mark}**

[]{.mark}

[[American Academy of Family Physicians]{.underline}]{.mark}

[DOUG CAMPOS-OUTCALT, M.D.]{.mark}

[University of Arizona, College of Medicine]{.mark}

[Phoenix, Arizona]{.mark}

[]{.mark}

[JONATHAN TEMTE, M.D.]{.mark}

[Family Practice Residency Program]{.mark}

[Madison, Wisconsin]{.mark}

[]{.mark}

[[American Academy of Pediatrics]{.underline}]{.mark}

[JOSPEH A. BOCCHINI, JR., M.D.]{.mark}

[Children\'s Hospital of LSU]{.mark}

[Shreveport, Louisiana]{.mark}

[]{.mark}

[[American College Health Association]{.underline}]{.mark}

[JAMES C. TURNER, M.D.]{.mark}

[Director, Elson Student Health Center]{.mark}

[University of Virginia]{.mark}

[Charlottesville, Virginia]{.mark}

[]{.mark}

[[American College of Obstetricians and
Gynecologists]{.underline}]{.mark}

[STANLEY GALL, M.D.]{.mark}

[University of Louisville School of Medicine]{.mark}

[Louisville, Kentucky]{.mark}

[]{.mark}

[[American College of Physicians]{.underline}]{.mark}

[GREGORY POLAND, M.D.]{.mark}

[Professor of Medicine, Infectious Diseases]{.mark}

[Rochester, Minnesota]{.mark}

[]{.mark}

[[American Geriatrics Society]{.underline}]{.mark}

[KENNETH SCHMADER, M.D.]{.mark}

[Duke University Medical Center]{.mark}

[Durham, North Carolina]{.mark}

[]{.mark}

[[American Medical Association]{.underline}]{.mark}

[LITJEN TAN, Ph.D.]{.mark}

[Director, Infectious Diseases, Immunology, & Molecular Medicine]{.mark}

[Chicago, Illinois]{.mark}

[]{.mark}

[[American Osteopathic Association]{.underline}]{.mark}

[STANLEY E. GROGG, D.O.]{.mark}

[Oklahoma State University]{.mark}

[Tulsa, Oklahoma]{.mark}

[]{.mark}

[[American Pharmacists Association]{.underline}]{.mark}

[STEPHAN L. FOSTER, Pharm.D.]{.mark}

[University of Tennessee, Memphis]{.mark}

[Memphis, Tennessee]{.mark}

[]{.mark}

[[America\'s Health Insurance Plans]{.underline}]{.mark}

[TAMARA LEWIS, M.D., M.P.H.]{.mark}

[Medical Director, Intermountain Healthcare]{.mark}

[Salt Lake City, Utah]{.mark}

[]{.mark}

[[Association for Prevention Teaching and Research]{.underline}]{.mark}

[PAUL MCKINNEY, M.D.]{.mark}

[Washington, D.C.]{.mark}

[]{.mark}

[[Biotechnology Industry Organization]{.underline}]{.mark}

[CLEMENT LEWIN, Ph.D., MBA]{.mark}

[Executive Director for Strategic Planning & Intelligence]{.mark}

[Chiron Vaccines]{.mark}

[Orange, Connecticut]{.mark}

[]{.mark}

[[Canadian National Advisory Committee on
Immunization]{.underline}]{.mark}

[JOANNE LANGLEY, M.D.]{.mark}

[Division of Infectious Diseases, Department of Pediatrics]{.mark}

[Canadian Center for Vaccinology]{.mark}

[Dalhousie University, Nova Scotia]{.mark}

[]{.mark}

[[Department of Health, United Kingdom]{.underline}]{.mark}

[DAVID SALISBURY, CB, FRCP, FRCPCH, FFPH]{.mark}

[London, England]{.mark}

[]{.mark}

[[Healthcare Infection Control Practices Advisory
Committee]{.underline}]{.mark}

[STEVE GORDON, M.D.]{.mark}

[Cleveland Clinic]{.mark}

[Cleveland, Ohio]{.mark}

[]{.mark}

[[Infectious Diseases Society of America]{.underline}]{.mark}

[SAM KATZ, M.D.]{.mark}

[Duke University Medical Center]{.mark}

[Durham, North Carolina]{.mark}

[]{.mark}

[[National Association of County and City Health
Officials]{.underline}]{.mark}

[JEFFREY DUCHIN, M.D.]{.mark}

[Chief, Communicable Disease Control]{.mark}

[Seattle, Washington]{.mark}

[]{.mark}

[[National Foundation for Infectious Diseases]{.underline}]{.mark}

[WILLIAM SCHAFFNER, M.D.]{.mark}

[Professor and Chairman]{.mark}

[Vanderbilt University School of Medicine]{.mark}

[Nashville, Tennessee]{.mark}

[]{.mark}

[[National Immunization Council and Child Health Program,
Mexico]{.underline}]{.mark}

[VESTA RICHARDSON, M.D.]{.mark}

[General Director]{.mark}

[National Center for Health and Infancy and Adolescence]{.mark}

[Colonia Merced Gomez, Mexico]{.mark}

[]{.mark}

[[National Medical Association]{.underline}]{.mark}

[PATRICIA WHITLEY-WILLIAMS, M.D.]{.mark}

[Chief, Pediatric Infectious Diseases]{.mark}

[Robert Wood Johnson Medical School]{.mark}

[New Brunswick, New Jersey]{.mark}

[]{.mark}

[[National Vaccine Advisory Committee]{.underline}]{.mark}

[GARY FREED, N.D., M.P.H.]{.mark}

[Division of General Pediatrics]{.mark}

[University of Michigan]{.mark}

[Ann Arbor, Michigan]{.mark}

[]{.mark}

[[Pharmaceutical Research and Manufacturers of
America]{.underline}]{.mark}

[DAMIAN A. BRAGA]{.mark}

[President, Sanofi Pasteur - U.S.]{.mark}

[Swiftwater, Pennsylvania]{.mark}

[]{.mark}

[PETER PARADISO, M.D.]{.mark}

[Vice President, Wyeth Vaccines]{.mark}

[Collegeville, Pennsylvania]{.mark}

[]{.mark}

[[Society for Adolescent Medicine]{.underline}]{.mark}

[AMY B. MIDDLEMAN, M.D., M.P.H.]{.mark}

[Baylor College of Medicine, Texas Children\'s Hospital]{.mark}

[Houston, Texas]{.mark}

[]{.mark}

[[Society for Healthcare Epidemiology of America]{.underline}]{.mark}

[HARRY L. KEYSERLING, M.D.]{.mark}

[Professor of Pediatrics, Emory University]{.mark}

[Atlanta, Georgia]{.mark}

[]{.mark}

[]{.mark}

**[CDC PARTICPANTS]{.mark}**

[]{.mark}

[Anne Schuchat, M.D.]{.mark}

[John Iskander, M.D.]{.mark}

[Nancy Messonnier, M.D.]{.mark}

[Jean Clare Smith, M.D., M.P.H.]{.mark}

[Greg Wallace, M.D.]{.mark}

[]{.mark}

**Acronyms**

AAP-American Academy of Pediatrics

ACIP-Advisory Committee on Immunization Practices

CDC-Centers for Disease Control and Prevention

CMS-Centers for Medicare and Medicaid Services

DHHS-Department of Health and Human Services

FDA-Food and Drug Administration

HCUP-Healthcare Utilization Project

HRSA-Health Resources and Services Administration

IOM-Institute of Medicine

ISO-Immunization Safety Office

NCHHSTP-National Center for HIV, Hepatitis, STD and TB Prevention

NCIRD-National Center for Immunization and Respiratory Diseases

NIH-National Institutes of Health

NVAC-National Vaccine Advisory Committee

[NVPO-National Vaccine Program Office]{.mark}

NVSN-New Vaccine Surveillance Network

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

VFC-Vaccines for Children

VSD-Vaccine Safety Datalink