Minutes for June 27, 2007

DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION

(CDC logo image)

Advisory Committee on Immunization Practices

June 27-28, 2007

Atlanta, Georgia

Record of the Proceedings

[]{.mark}

[Day 1, June 27, 2007]{.mark}

[]{.mark}

[WELCOME AND INTRODUCTION]{.mark}

[Dr. Abramson]{.mark}

[Dr. Pickering]{.mark}

[Dr. Abramson]{.mark}

[HEPATITIS A VACCINE]{.mark}

[Introduction: Dr. Lieu]{.mark}

[Postexposure and]{.mark}

[Travel Prophylaxis: Dr. Novak]{.mark}

[Vote]{.mark}

[Travel Recommendations: Dr. Novak]{.mark}

[Vote]{.mark}

[VFC Vote: Dr. Calugar]{.mark}

[VACCINE FINANCING]{.mark}

[Underinsured Children: Dr. Lee]{.mark}

[AMA/AAP Immunization Congress: Dr. Orenstein]{.mark}

[NVAC Financing Working Group: Dr. Birkhead]{.mark}

[PROPOSED REVISIONS TO THE ADULT IMMUNIZATION SCHEDULE]{.mark}

[Introduction: Dr. Morse]{.mark}

[Information: Dr. Mootrey]{.mark}

[Vote]{.mark}

[PROPOSED REVISIONS TO THE CHILDHOOD/ADOLESCENT SCHEDULE]{.mark}

[Information: Dr. Calugar]{.mark}

[CDC IMMUNIZATION SAFETY UPDATE]{.mark}

[Information: Dr. Broder]{.mark}

[HERPES ZOSTER (SHINGLES) VACCINE]{.mark}

[Introduction: Dr. Treanor]{.mark}

[Information: Dr. Chaves]{.mark}

[]{.mark}

[COMBINATION VACCINES]{.mark}

[Activities and Next Steps: Ms. Stinchfield]{.mark}

[MENINGOCOCCAL CONJUGATE VACCINE (MCV4)]{.mark}

[Introduction: Dr. Baker]{.mark}

[Epidemiology: Dr. Cohn]{.mark}

[Economic Model of Expansion: Dr. Ortega-Sanchez]{.mark}

[Vaccine Supply, Private Sector: Mr. Hosbach]{.mark}

[Vaccine Supply, Public Sector: Dr. Wallace]{.mark}

[Vaccine Safety: Dr. Iskander]{.mark}

[New Recommendations: Dr. Cohn]{.mark}

[Vote]{.mark}

[]{.mark}

[ECONOMIC ANALYSES OF VACCINES]{.mark}

[Introduction: Dr. Lieu]{.mark}

[Discussion: Dr. Mark Messonnier]{.mark}

[]{.mark}

[VACCINE SUPPLY AND IMPLEMENTATION]{.mark}

[Information: Dr. Wallace]{.mark}

[PNEUMOCOCCAL VACCINES]{.mark}

[Working Group Information: Dr. Morita]{.mark}

[VACCINES DURING PREGNANCY/BREAST-FEEDING]{.mark}

[Introduction: Dr. Neuzil]{.mark}

[Information: Dr. Schrag]{.mark}

[Information: Dr. Skoff]{.mark}

[]{.mark}

[Day 2, June 28, 2007]{.mark}

[]{.mark}

[INFLUENZA VACCINES]{.mark}

[Introduction and Update on LAIV: Dr. Fiore]{.mark}

[FluMist Safety Monitoring: Dr. Broder]{.mark}

[National Influenza Vaccine Summit: Dr. Mootrey]{.mark}

[USE OF VACCINES IN PERSON WITH HIV/AIDS]{.mark}

[Children and Adolescents: Dr. Seward]{.mark}

[Vote]{.mark}

[Adults: Dr. Mootrey]{.mark}

[UPDATE: ROTAVIRUS VACCINES]{.mark}

[Introduction: Dr. Treanor]{.mark}

[VAERS and VSD: Dr. Haber]{.mark}

[Data Interpretation: Dr. Patel]{.mark}

[RotaTeq and Kawasaki Disease: Dr. Izurieta]{.mark}

[]{.mark}

[UPDATE: HPV VACCINES]{.mark}

[Introduction: Dr. Gilsdorf]{.mark}

[Safety Update: Dr. Iskander]{.mark}

[Quadrivalent Safety Update: Dr. Dubin]{.mark}

[Future Considerations: Dr. Markowitz]{.mark}

[UPDATE: VARICELLA]{.mark}

[Arkansas Outbreak: Ms. Lopez]{.mark}

[AGENCY UPDATES]{.mark}

[PUBLIC COMMENT]{.mark}

List of Participants and Attendees

List of Acronyms

**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**CENTERS FOR DISEASE CONTROL AND PREVENTION**

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

**June 27-28, 2007**

### Atlanta, Georgia

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

The Department of Health and Human Services (HHS) and the Centers for
Disease Control and Prevention (CDC), National Center for Immunization
and Respiratory Diseases (NCIRD) convened a meeting of the Advisory
Committee on Immunization Practices (ACIP). The meeting was held on June
27-28, 2007 at CDC's Global Communications Center in Atlanta, Georgia.
The list of participants is appended to the minutes as [Attachment
1]{.underline}. \[Note: the list only includes persons who introduced
themselves for the record, presented, made public comments, or
registered prior to the meeting.\]

[]{.mark}

**[Day One, June 27, 2007]{.mark}**

[]{.mark}

**[[WELCOME AND INTRODUCTION]{.underline}]{.mark}**

[]{.mark}

[Dr. Abramson welcomed attendees to the June 2007 ACIP meeting. Dr.
Pickering introduced several international visitors, including Dr.
Christine Ding-Ping Liu, Director of the Vaccine Center for the Centers
of Disease Control in Taiwan, and members of the Turkish Adult
Immunization Advisory Board. In addition, he welcomed the new liaison
representative from Canada\'s National Advisory Committee on
Immunization Practices, Dr. Joanne Langley from the Division of
Infectious Diseases of the Department of Pediatrics, the Canadian Center
for Vaccinology at Dalhousie University in Nova Scotia, and thanked Dr.
Monika Naus, who was replaced by Dr. Langley. He noted several people
who could not attend the meeting, including ACIP member Dr. Robin
Womeodu. Dr. Geoff Evans was not present, but Dr. Indira Jevaji took his
place; Dr. Norm Baylor was not present, but Dr. Florence Houn attended
on his behalf; Dr. Wayne Hatchey from the Department of Defense was
represented by Dr. Ted Cieslak; and neither Dr. Paul McKinney from the
Association of Teachers of Preventive Medicine nor Dr. David Salisbury
from the Department of Health in London were able to attend. Finally,
Dr. Pickering announced that Dr. Sam Katz had been awarded a 2007 Pollin
Prize for his contributions to pediatric infectious diseases and vaccine
development, particularly his role in developing the measles vaccine
with Nobel laureate Dr. John Enders.]{.mark}

[Dr. Pickering noted that the CDC web site had been revised and that the
ACIP site is updated frequently with the current version of the meeting
agenda, meeting minutes and presentations, ACIP recommendations and
other ACIP activities
(]{.mark}<http://www.cdc.gov/vaccines/recs/acip/default.htm> )[.]{.mark}

[Dr. Pickering explained that the goal in appointing members to the ACIP
is to achieve the greatest level of expertise while minimizing the
potential for actual or perceived conflicts of interest. To summarize
conflict-of-interest provisions applicable to the ACIP, as noted in the
Policies and Procedure manual, members of the ACIP agree to forgo
participation in certain activities related to vaccines during their
tenure on this committee. For certain other interests that potentially
enhance a member\'s expertise while serving on the committee, CDC has
issued limited conflict-of-interest waivers. Members who conduct
clinical vaccine trials or serve on safety data monitoring boards may
serve as consultants to present to the committee on matters related to
those vaccines. However, they are prohibited from participating in the
deliberations or votes of the committee on issues related to those
specific vaccines. Regarding other vaccines of an affected company, a
member may participate in discussions with the proviso that he or she
abstains on all votes related to the vaccines of that company. ACIP
members who may have a potential conflict of interest should make it
known by disclosing all of their vaccine-related financial interests and
work.]{.mark}

[Dr. Abramson noted that the terms of four members, including himself,
would expire on June 30th. He presented those members with a certificate
of appreciation and thanked them for their many contributions to ACIP
over the years. Dr. Ban Allos, Dr. Janet Gilsdorf, and Dr. John Treanor
all spoke briefly about what working on the committee had meant to
them.]{.mark}

[Dr. Abramson added his appreciation of the incredible talent found
among the ACIP committee members, the liaisons, and particularly the
full-time CDC staff. He then pointed out some of the accomplishments he
had witnessed, starting in 1999, when thimerosal was becoming an
important topic and rotavirus vaccine was causing problems over the
issue of intussusception. Influenza vaccine has gone to an age-based
rather than a risk-based recommendation and appears to be moving toward
a universal recommendation for all children, if not for adults. Progress
has been made on the ACIP-HICPAC joint statement on immunization of
healthcare workers, but that needs further emphasis.]{.mark}

[In 1999 the committee voted to stop the use of rhesus rotavirus vaccine
in the U.S., with the understanding that the risk-benefit ratio differed
tremendously from that of developing countries. However, manufacturers
developed other safer rotavirus vaccines, which will be introduced into
developing countries in the next few years.]{.mark}

[The committee approved varicella zoster recommendations that now
include the use of a routine second dose and will be looking at its
impact on decreasing the occurrence of varicella disease and fixing the
age shift in the occurrence of the disease. The recommended use of MMRV,
despite occasional vaccine shortages, will help decrease the number of
injections that children need. The herpes zoster vaccine is aimed
specifically at older adults and is now recommended for routine
use.]{.mark}

[The development of an adolescent platform was a major move forward,
especially use of a conjugated meningococcal vaccine. Tdap was
recommended for use in adolescents as well as adults and healthcare
providers. The pertussis component of this combination vaccine will have
more impact now that it is being used in adolescents and adults. The
impact of the human papillomavirus vaccine, the first vaccine
specifically created as an anticancer vaccine, will be great; the issue
of how to implement it remains to be solved.]{.mark}

[The recommendation for use of hepatitis B vaccine in adults has been
expanded, and perhaps should be expanded further. The hepatitis A
recommendation also has been expanded to include all children 12 months
of age and older, which has already shown a marked impact due to the
high-risk part of the recommendation. The committee has continued to
make recommendations based on good science and the best interest of the
United States, without regard to cost. However, there is much to be done
in the area of vaccine financing.]{.mark}

[]{.mark}

[**Dr. Pickering** thanked Dr. Abramson for all his work as chair of
ACIP and as a member of the influenza work group. He praised Dr.
Abramson's intellect and insight, as well as his compassion and
integrity -- particularly his concern for children and adults.]{.mark}

[]{.mark}

[**Dr. Abramson** asked committee members to state any conflicts of
interest.]{.mark}

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

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

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

[Dr. Gilsdorf said she was an independent safety monitor on an
NIH-sponsored vaccine trial for which she receives no
compensation.]{.mark}

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

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

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

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

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

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

[Dr. Treanor said he was doing clinical trials of influenza vaccines for
Protein Sciences and for Merck, and had laboratory support for influenza
work from GlaxoSmithKline.]{.mark}

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

[Dr. Abramson said he had no conflicts, but was on an NIH data safety
monitoring board for the use of oseltamivir in children less than one
year old.]{.mark}

[]{.mark}

[Dr. Pickering announced that there would be four new members joining
the ACIP beginning July 1st and a fifth new member would be appointed in
the very near future. The new members are Dr. Lance Chilton, a
pediatrician with the Young Children\'s Health Center and Professor of
Pediatrics at the University of New Mexico in Albuquerque; Dr. Paul
Cieslak, Medical Director of the Oregon Immunization Program, Oregon
State Public Health Division and Clinical Assistant Professor in Public
Health and Preventive Medicine and Iinfectious Diseases at the Oregon
Health and Science University; Dr. Allen Craig, State Epidemiologist
from the Tennessee Department of Health, trained in family medicine; and
Dr. Janet Englund, Associate Professor of the Division of Pediatric
Infectious Diseases at Children\'s Hospital, the University of
Washington and Fred Hutchinson Cancer Research Center in Seattle. As of
July 1st, the new ACIP Chair will be Dr. Dale Morse, who has been an
ACIP member since July of 2005. Dr. Morse is Director of the Office of
Science and Public Health at the New York State Health Department. He
will be assisted by Dr. Carol Baker, who will serve as the Vice Chair.
Dr. Baker has been an ACIP member since July of 2006 and is Professor of
Pediatrics, Molecular Virology, and Microbiology at Baylor College of
Medicine.]{.mark}

[]{.mark}

**[[HEPATITIS A VACCINE: POSTEXPOSURE AND TRAVEL
PROPHYLAXIS]{.underline}]{.mark}**

**[Dr. Tracy Lieu, ACIP, WG Chair]{.mark}**

**[Dr. Ryan Novak, CDC/NCHHSTP/DVH]{.mark}**

[]{.mark}

[**Dr. Lieu** began with a reminder that the ACIP had considered draft
recommendations for postexposure prophylaxis for hepatitis A in February
and at that time it was apparent that more clarification and discussion
were needed. An ACIP hepatitis working group was formed and was able to
reach consensus on the wording of the recommendations with the hepatitis
group within CDC. For postexposure prophylaxis for persons 12 months to
18 years old, vaccine is preferred to immune globulin (IG). For persons
19 to 40 years old, vaccine is preferred to IG. For persons over 40
years old, IG is preferred although vaccine can be used if IG cannot be
obtained. Lastly, for patients with chronic liver disease, those who are
immunocompromised, and children less than 12 months old, IG should be
used.]{.mark}

[These recommendations also affect the recommendations for hepatitis A
travel vaccinations. Based on new data on vaccine effectiveness
postexposure, the recommendation is that the first dose of vaccine at
any time before travel should protect most healthy persons. Another
recommendation is to add immune globulin for high-risk groups who are
traveling in less than two weeks to areas of high transmission and to
use IG for persons less than 12 months old or who cannot receive
vaccine.]{.mark}

[]{.mark}

[**Dr. Novak** summarized the conclusions from the February ACIP meeting
when these data were first introduced, as well as the activities of the
hepatitis work group. In February, Dr. John Victor presented the results
of a clinical trial comparing efficacy of hepatitis A vaccine and immune
globulin after exposure. This was followed by a discussion of these data
and the policy implications of using hepatitis A vaccine alone
postexposure. The work group reviewed the available data with respect to
vaccine age groups and patients with chronic liver disease and other
underlying medical conditions. It considered patient characteristics
associated with more severe outcomes, response to vaccine, and the risk
of transmission in common scenarios where postexposure prophylaxis is
given in the U.S., and then drew on the experiences of those countries
currently using hepatitis A vaccine post exposure.]{.mark}

[Potential benefits of being able to use vaccine include long-term
protection, ease of administration, acceptability, and availability.
There is currently only one U.S. supplier of immune globulin, and the
cost of IG has risen considerably over the last five to ten years,
making it similar to that of hepatitis A vaccine. A single adult dose of
IG is now about \$20, and the pediatric vaccine dose under government
contract is about \$12. The adult dose is about \$19. Another benefit of
being able to use hepatitis A vaccine is that it brings U.S. practice in
line with many other countries that recommend vaccine as postexposure
prophylaxis.]{.mark}

[In the randomized clinical non-inferiority hepatitis A vaccine
postexposure trial conducted in Almaty, Kazakhstan, 4,524 households or
day-care contacts aged 2 to 40 years were enrolled. Contacts had been
exposed to index cases within two weeks after the index case symptom
onset and had no history of hepatitis A or receipt of hepatitis A
vaccine or IG within the last six months, chronic liver disease, or
contraindications to vaccine or IG. There was a 1-to-1 randomization
within households or day-care centers to receive vaccine or IG within
two weeks after the index case symptom onset. The primary outcome was
clinical hepatitis A among contacts that met the following three
criteria: Positive for IgM anti-HAV, ALT level at least twice the upper
limit of normal during an episode of illness with no other obvious
cause, and symptoms consistent with viral hepatitis.]{.mark}

[The results of that study indicated that the efficacy of hepatitis A
vaccine was similar to that of IG, i.e., the noninferiority criterion
was met. Because of the study design, the point estimate for vaccine
efficacy required an assumption about IG efficacy. Assuming 90 percent
IG efficacy, the point estimate of vaccine efficacy was 86 percent with
a 95 percent confidence interval of the upper bound of the relative risk
of 76 percent. If 85 percent IG efficacy was assumed, the point estimate
of vaccine efficacy was 80 percent with the upper bound of 64
percent.]{.mark}

[Despite showing statistical noninferiority, the proportion of outcomes
among vaccine recipients was slightly higher than among IG recipients,
however the difference was small. Putting this in context, the risk of
hepatitis A among vaccine recipients was never more than 1.5 percent
greater than among IG recipients. This study provided evidence
consistent with many previous studies that IG might attenuate clinical
illness when given after exposure.]{.mark}

[Looking at clinical endpoints by age, most cases were among children,
so that was where the most inference was made, however the estimates for
adults were similar. For the primary endpoint, 26 cases of
laboratory-confirmed hepatitis A occurred among vaccine recipients and
18 occurred among IG recipients, yielding a relative risk among vaccine
versus IG of 1.32. The one-sided 95 percent confidence interval upper
bound of relative risk was 2.3, which was well within the prespecified
margin of 3.0.]{.mark}

[When stratified by age, the risk of hepatitis A was slightly higher
among adults than in children in both the IG and vaccine groups. The
point estimate of the relative risk for adults was very similar to that
among children, but because of the relatively small number of adult
participants, this stratified analysis has low power, so the confidence
interval is wide. Similar findings were found when considering all
suspected hepatitis A cases.]{.mark}

[After considering these results, the consensus of the work-group
members was that there was sufficient evidence to support equivalency of
vaccine and IG in both children and adults 40 years or younger. Because
of the advantages of vaccine and equivalence to IG, the work group
decided to state a preference for vaccine in this age group: *"For
healthy persons age greater than or equal to 12 months to 40 years,
hepatitis A vaccine at the age appropriate dose is preferred to IG
because of vaccine's advantages, including long term protection and ease
of administration."*]{.mark}

[At the time the Almaty study began, hepatitis A vaccine was not yet
licensed down to 12 months in the U.S., thus children aged 12 to 24
months were excluded from the study population. The work group decided
to include 12- to 23-month-olds in the vaccine recommendations. There is
no evidence to suggest persistence of maternal antibody past 12 months,
and the immunogenicity of the vaccine at 12 months is similar to that of
24 months. Currently, vaccine is licensed for use from 12 months in
every country with a hepatitis A vaccine immunization program. Finally,
current ACIP recommendations include this age group for pre-exposure
vaccine use.]{.mark}

[Unfortunately, results of the current study and previous information
cannot answer all questions about how hepatitis A performs postexposure.
First there is the question of age. Eligibility was restricted to age 40
and under in the Kazakhstan study. Most of the cases and study
participants were fairly young, which is not surprising, given the
epidemiology of hepatitis A in a country like Kazakhstan. All adults
over age 40 are immune to hepatitis A, as are many young adults. No
additional data are available to support preference for vaccine in these
risk groups.]{.mark}

[Considering the clinical characteristics of reported hepatitis A cases
by age in 2005 received through the National Notifiable Disease
Surveillance System (NNDSS), the severity of hepatitis A disease
increases with increasing age, as evidenced by the proportion of
hospitalizations and deaths due to hepatitis A. Because of the absence
of data about vaccine performance in persons older than 40 years and the
risk of hepatitis A increasing with age, the work group made the
following recommendation: *"For persons greater than 40 years, IG is
preferred because of the absence of information regarding vaccine
performance and the more severe manifestations of hepatitis A in this
age group. Vaccine can be used if IG cannot be obtained." *]{.mark}

[The next population addressed was persons who were diagnosed with
chronic disease, immunocompromised, and people with other medical
conditions. The Almaty study excluded patients who reported a diagnosis
of chronic liver disease based on the concern about the increased
severity of hepatitis A. It did not explicitly exclude people with other
medical conditions, but in general the study population was young and
healthy. Patients with chronic liver disease or other chronic medical
conditions are known to have poorer response to vaccine pre-exposure. In
addition, patients with chronic liver disease have a higher risk of more
severe disease outcomes.]{.mark}

[Dr. Novak then presented available data with respect to immune response
to a single hepatitis A dose in selected populations. Among HIV-infected
patients, the three relevant studies report a wide range of
seroconversion after one dose of hepatitis A: from 10 percent to 78
percent. Hepatitis A vaccination is recommended for patients with
chronic liver disease, so there has been a fair amount of interest in
studying the immunogenicity of the vaccine in these patients. In the
three published studies of immunogenicity in these patients, the percent
positive at four weeks ranges from 63 to 93 percent. It appears that the
response rate is lowest in patients with decompensated cirrhosis.
Finally, a few studies in liver and kidney transplant patients showed a
much lower percent positive at four weeks.]{.mark}

[A number of studies have indicated that the risk of severe outcomes
from hepatitis A is higher among people with chronic liver disease
(CLD). In a recent analysis of national death certificate data from 1999
to 2004 among 511 hepatitis A deaths, 229, or 45 percent, of deaths
included a CLD-related ICD-10 code. The median age was 55 among
CLD-related deaths and 69 among non-CLD-related deaths. Because of the
suggestion of a suboptimal response to hepatitis A vaccine and the
increased risk of severe hepatitis A outcomes in CLD patients, the work
group decided to leave the current recommendation for IG in these
groups: *"IG should be used for children age less than 12 months,
immunocompromised persons, persons who have been diagnosed with chronic
liver disease, and persons for whom vaccine is
contraindicated."*]{.mark}

[The work group also reviewed the risk of transmission of hepatitis A
virus and the common scenarios in which postexposure prophylaxis is
given in the U.S. The most common setting for IG use as a postexposure
prophylaxis currently is among household and other close personal
contacts. Outbreaks in childcare centers used to require IG, but now
these outbreaks are rare. In these settings, secondary attack rates of
15 to 30 percent are common, with higher rates of transmission occurring
from infected young children than from adolescents and adults. This is
probably the setting in which the risk of transmission is
highest.]{.mark}

[Another common scenario is after exposure to an infected food handler.
Based on surveillance data, 3 to 7 percent of reported hepatitis A cases
are food handlers. About 5 percent of food handlers worked while they
were infectious and were felt to pose a transmission risk, i.e., people
who might have been exposed to this food handler should be notified.
However, the majority of food handlers do not transmit to patrons, as
attack rates are generally low. In the context of these public
notifications, an average of 350 IG doses per episode were administered.
But there is a very broad range, and thousands of people received IG.
The ability to use a vaccine might be quite beneficial in these
circumstances.]{.mark}

[Thus the working group recommended the following language: *\"Decisions
to use vaccine or IG should take into account patient characteristics
associated with more severe manifestations of hepatitis A. Additionally,
the magnitude of the risk of hepatitis A virus transmission from the
exposure should be considered.\" *]{.mark}

[At the last meeting the committee heard about postexposure policies of
Canada, the UK, and other European countries. The work group looked for
new data, and reconsidered available data with respect to the experience
in Canada and the UK. In Canada, vaccine without IG is the preferred
method of postexposure prophylaxis, while IG continues to be used for
infants and the immunocompromised. The work group reviewed one report of
possible breakthrough infections, but it was found to be a transmission
chain involving outbreaks in several child day-care settings. It also
tried to get additional information about the rationale of the U.K.
recommendations, which limit vaccine to exposures within the previous
seven days and IG for exposures greater than seven days or involving
people older than 50 years with cirrhosis or chronic HBV or HCV
infections. But the data available to inform these recommendations were
very limited.]{.mark}

[In summary, vaccine offers a number of advantages over IG, and the
flexibility to use vaccine in some circumstances would be beneficial.
Available data suggest that vaccine is efficacious postexposure, but not
all populations were studied. Pre-exposure immunogenicity data suggest
that there are suboptimal responses to vaccine in persons with chronic
liver disease and other chronic medical conditions. Any recommendation
the committee might make about the ability to use vaccine would be an
off-label use, as it is not approved through FDA for this indication.
Additional data are not likely to be forthcoming, and additional studies
would be logistically difficult. So the committee needs to balance the
practical public health implementation considerations against the
limitations of the available information.]{.mark}

[Among the materials provided to the committee was a copy of the current
postexposure prophylaxis ACIP statement to provide background, as well
as the new recommendations for postexposure prophylaxis. This document
is meant to be a stand-alone MMWR 'notice to readers' with links to and
from the current ACIP hepatitis A statement, thus it contains an
introduction to the recommendation language to provide background
information to the reader as to what changes were made and their
rationale. These recommendations were clarified by appending the
language from the current statement concerning common settings in which
postexposure prophylaxis is given in the U.S. The only language change
is the substitution of *"IG or hepatitis A vaccine"* for *"IG."* In
addition, the committee was provided with new travel recommendations for
timing of pre-exposure vaccine dose.]{.mark}

[The draft language for postexposure prophylaxis with hepatitis A
vaccine is as follows: *\"Persons who recently have been exposed to
hepatitis A virus and who previously have not received hepatitis A
vaccine should be administered a single dose of vaccine or IG as soon as
possible. Information about the relative efficacy of vaccine compared to
IG postexposure is limited, and no data are available in persons aged
greater than 40 years or those with underlying medical
conditions.*]{.mark}

*[\"Therefore, decisions to use vaccine or IG should take into account
patient characteristics associated with more severe manifestations of
hepatitis A, including older age and chronic liver disease.
Additionally, the magnitude of the risk of hepatitis A virus
transmission from the exposure should be considered.\"]{.mark}*

[The next paragraphs deal with specific groups. *\"For healthy persons
age greater than or equal to 12 months to 40 years, hepatitis A vaccine
at the age appropriate dose is preferred to IG because of the vaccine\'s
advantages, including long-term protection and ease of
administration.*]{.mark}

*[\"For persons greater than 40 years, IG is preferred because of the
absence of information regarding vaccine performance and the more severe
manifestations of hepatitis A in this age group. Vaccine can be used if
IG cannot be obtained.]{.mark}*

*[\"IG should be used for children age less than 12 months,
immunocompromised persons, persons who have been diagnosed with chronic
liver disease, and persons for whom vaccine is contraindicated.]{.mark}*

*[\"Persons administered IG for whom hepatitis A vaccine is also
recommended should receive a dose of vaccine simultaneously with IG. For
persons who receive vaccine, the second dose should be administered
according to the licensed schedule to complete the series. The efficacy
of IG or vaccine when administered greater than two weeks after exposure
has not been established.\"]{.mark}*

[]{.mark}

**[Discussion]{.mark}**

[Dr. Allos asked whether adults over 40 who received IG as postexposure
prophylaxis could also receive the vaccine and, if so, whether that
should that be made part of the recommendation.]{.mark}

[Dr. Neuzil was concerned about not having comparative
randomized-controlled data on persons over 40. Looking at the
hospitalization rates from the 15 to 39 group and the 40 to 59, the real
jump seemed to occur at 60 and over. Thus she wondered what data would
be sufficient to recommend vaccine above the age of 40 or whether there
were immunogenicity data in immunocompetent healthy people between 40
and 59 that could be used as a bridge. Dr. Novak replied that there were
not enough data to inform that decision currently, nor are there any
data in the pipeline. Dr. Neuzil added that if immunogenicity data would
be helpful, those are relatively easy and inexpensive studies to
do.]{.mark}

[Dr. Barbara Kuter reported that Merck did look at immunogenicity in
individuals greater than 40, and in fact their dosage is different from
individuals less than 40 because the response with the 25-unit dose was
not as good. They moved to the 50-unit dose, for which there are data in
individuals over 40, and seroconversion rates are comparable to those
less than 40.]{.mark}

[Dr. Lett expressed concern about having so many age stratifications,
which complicates the public health response when clinics have to
rapidly vaccinate hundreds or thousands of people, particularly for
restaurant exposures. The data about lack of transmission to patrons
were interesting in that respect. Dr. Novak said those data were partly
why the recommendations state a preference for IG , but that vaccine
could be used if IG was not available. With situations such as
restaurant exposures where the risk of transmission is believed to be
low, vaccine could be used in older individuals. The worry is that older
individuals with potentially underlying medical conditions that
predispose them for more severe manifestations really need to receive
IG. Dr. Abramson suggested that since serologic bridging data would not
be published until October, that specific issue could be voted on
October and put in the final document.]{.mark}

[Dr. Hull asked whether only a single dose was being recommended
postexposure. Dr. Novak clarified that a single dose was sufficient for
postexposure prophylaxis but the second dose should be administered
according to the licensed schedule to complete the series. Dr. Baker
pointed out that exposed individuals who had had the vaccine series
would not need postexposure prophylaxis. Dr. Abramson added that having
had proven hepatitis A should also preclude needing vaccine.]{.mark}

[Dr. Treanor asked whether having been involved in an outbreak or other
situations where prophylaxis was required, such as travel, would
identify one as being at higher risk of subsequent exposures to
hepatitis A than the general population. In other words, why would it
matter whether they got the second dose? Dr. Treanor responded that it
was just a question of logic.]{.mark}

[Dr. Schuchat noted that this country had already moved to a universal
hepatitis A strategy, so the issue of high risk and low risk has changed
because of the safety, effectiveness, and long-term protection of the
vaccine.]{.mark}

[Dr. Hull said he was confused by the statement indicating that the
intensity of exposure should be considered in making the decision for IG
versus vaccine. Dr. Novak replied that the recommendations needed to be
seen in context. They include definitions for different settings where
hepatitis A postexposure is often used in the U.S. and this provides
some guidance as to the magnitude of risk. Household or close contact
might be considered high risk versus the low risk of transmission in the
case of an exposure to an infected food handler. Dr. Hull asked whether
someone with high-risk exposure should get IG or vaccine. Dr. Novak
explained that the magnitude of risk question pertains only to those
individuals over 40 years of age, for which there are no efficacy data.
For those people, one might use IG if there was a household or
close-contact situation and vaccine if it was an exposure to an infected
food handler, except where contraindicated. The recommendations are
clear that persons at higher risk for more severe complications of
hepatitis A should be receiving IG. Dr. Hull agreed with the context
idea, but still felt the recommendation should be more explicit.]{.mark}

[Dr. Morse asked whether one would be able to get data on safety and
efficacy for people over age 40 from other countries. Dr. Abramson said
he felt most people would feel comfortable with serologic data as a
bridge.]{.mark}

Dr. Treanor pointed out that the statement actually says one should take
into account the magnitude of the risk of transmission independently of
the magnitude of the severity of disease and asked how that would be
used to decide between the vaccine or IgG. Dr. Novak commented that the
most common interactions with the state health departments were around
helping decide the risk to those exposed. Dr. Bennett added that the
decision was complex, but that it came down to whether or not to give
prophylaxis and the statement needed to be simpler for the people giving
the vaccine.

Dr. Bennett asked a related question about the timing of immune globulin
and vaccine and whether immune globulin can be given after the vaccine
if it is not available initially. Dr. Novak replied that that the work
group had not specifically addressed this issue, but the important thing
would be to get some kind of postexposure intervention put in place
right away if it was a high-risk exposure. Dr. Hull pointed out that the
language should clarify that this applies only to high-risk individuals.
[Dr. Pickering restated the previous question: If a person gets vaccine
and then gets immune globulin, will the immune globulin inactivate the
hepatitis A vaccine such that the whole series would have to be
repeated? Dr. Bell responded that when vaccine and IG are administered
simultaneously, the data indicate that the geometric mean concentrations
from vaccine are somewhat lower. Other situations also suggest that when
antibody is given, immunogenicity is reduced. Nonetheless, the antibody
concentrations are still quite high, so there is no problem giving
vaccine and IG at the same time. She speculated that there might be
fewer problems giving IG after vaccine than giving IG with
vaccine.]{.mark}

[An unidentified speaker commented that the stratification seemed rather
complicated and suggested having one broad recommendation, with a guide
for practitioners regarding the quality of evidence for one age group or
another.]{.mark}

[Dr. Bell said she appreciated the concern about bridging immunogenicity
data, but felt the committee would need to be clear about what
pre-exposure data would be relevant to the performance of vaccine
postexposure. There are few data available with respect to pre-exposure
immunogenicity in people older than 40. One could argue that the
relevant]{.mark} information is response at two weeks after the first
dose of vaccine, and that available [evidence showing seroconversion at
four weeks after a single dose of vaccine with differences in geometric
mean concentrations in older versus younger adults might not be adequate
bridging immunogenicity data to confidently recommend the equivalence of
vaccine versus IG in people older than 40. She added a word of caution
about whether bridging immunogenicity data in people over 40 would
address the concern about the performance of vaccine in that age group.
It is not as simple as stating that since there is 90 percent
seroconversion at four weeks, vaccine works as well as IG
postexposure.]{.mark}

[Dr. Lieu asked whether the immunogenicity data presented for the
older-than-40 age group in February were the same as that from Merck.
Dr. Bell replied that the Merck data were not published, and that the
data she presented used the previously licensed GlaxoSmithKline
formulation, which is a three-dose series at half the dosage per shot,
so they were not helpful for looking at the postexposure performance of
a single dose at double. One published study explicitly looked at less
than age 40 versus over 40 and at two weeks after the first dose; there
was a difference in the percent positive between people less than 40 and
older than 40, as well as a difference in the GMT. By four weeks, that
difference closed up to about 70 percent positive at two weeks after one
dose of vaccine in people older than 40, as opposed to 90-plus percent
positive. One could argue that this is relevant when considering using
vaccine in a postexposure setting. Dr. Kuter confirmed that the amount
of data at the two-week time point was limited. The information at four
weeks is much more substantial.]{.mark}

[Dr. Abramson asked whether anyone still wanted to look at those data
and to see if the recommendation as far as age cutoff should be changed.
When there was no response, he felt the committee was ready to vote on
the recommendation to preferentially vaccinate one-year-olds to
40-year-olds and to use IG in the other settings.]{.mark}

[]{.mark}

**[Vote]{.mark}**

[Dr. Morse made a motion in favor of the recommendation, which Dr. Baker
seconded.]{.mark}

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

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

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

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

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

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

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

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

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

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

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

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

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

[]{.mark}

[Dr. Abramson reminded the committee members they would have a chance to
look at this document before it was finalized and published and make
comments about specific issues. Dr. Baker commented that, with respect
to the over-40 group, it would be nice to get convincing data because
that would make it easier operationally for everyone.]{.mark}

[]{.mark}

**[Travel Recommendations]{.mark}**

[**Dr. Novak** presented the travel recommendations, which needed to be
revised to bring them in line with the changes just voted on. The
current ACIP travel recommendations for preexposure protection against
hepatitis A state that travelers departing in more than four weeks
should receive vaccine. If departure is within two to four weeks, then
IG may be given for optimal protection. IG is recommended for children
less than 12 months old, and persons allergic to or electing not to
receive vaccine.]{.mark}

[The work group found that the Almaty study findings and the new
postexposure recommendations were relevant to preexposure vaccine use
among at-risk travelers. The data regarding postexposure use suggest
vaccine administered any time prior to departure should adequately
protect most travelers, but may not be generalizable to all
populations.]{.mark}

[The actual recommendation begins, *\"The first dose of hepatitis A
vaccine should be administered as soon as travel is considered. Based on
limited data showing equivalent postexposure efficacy of IG and vaccine
among healthy persons aged less than or equal to 40 years, one dose of
single-antigen hepatitis A vaccine administered at any time before
departure may provide adequate protection for most healthy individuals.
*]{.mark}

*[\"However, no data are available for other populations or other
vaccine formulations. For optimal protection, older adults,
immunocompromised persons, and persons with chronic liver disease or
other chronic medical conditions traveling to an area where risk of
transmission is high less than two weeks after the initial dose, may
also be administered IG, but at a different anatomic injection site.
Completion of the vaccine series according to the licensed schedule is
necessary for long-term protection.\"]{.mark}*

[There is no change in the rest of the recommendation, which reads as
follows: *\"Travelers who elect not to receive vaccine or are less than
12 months of age or allergic to a vaccine component should receive a
single dose of IG, which provides effective protection against hepatitis
A for up to three months. Travelers whose travel period is greater than
two months should be administered IG, and administration must be
repeated if the travel period is greater than five months.\"*]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Mobeen Rathore noted that there was a time period of greater than
four weeks for first line, then another one of two to four weeks. He
thought just saying 'less than four weeks' would be easier for people in
the field, unless there were specific differences between two and four
weeks.]{.mark}

[Mr. Beck asked about people who have liver disease or are
immunocompromised, as covered in the previous recommendation. Dr. Novak
said they should receive IG.]{.mark}

[]{.mark}

**[Vote]{.mark}**

[Dr Abramson asked for a motion to accept the travel recommendations.
Dr. Hull so moved and Dr. Gilsdorf seconded the motion.]{.mark}

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

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

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

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

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

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

[Dr. Lieu : yes.]{.mark}

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

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

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

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

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

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

[]{.mark}

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

[**Dr. Calugar** reminded the committee that the vaccine-specific
resolutions for the Vaccines for Children Program, or VFC, are revised
any time there is a new or updated ACIP recommendation. For the
just-approved postexposure use of hepatitis A vaccine, there were
changes relating to eligible groups, but the recommended hepatitis A
schedule and dosage intervals remained unchanged. A new section was
incorporated in the VFC resolution, *\"Recommendation for use of
hepatitis A vaccine for postexposure prophylaxis,\"* which is similar to
the just-approved ACIP recommendations.]{.mark}

[The first paragraph includes general information about administering
immune globulin and a statement about limited relative efficacy data
when administrating hepatitis A vaccine compared to IG post exposure.
The complex picture of a person\'s health condition, including age and
chronic liver disease, as well as the magnitude of the risk of hepatitis
A virus transmission, should be considered in this decision
process.]{.mark}

[Specifics are needed for postexposure prophylaxis in selected special
categories. Immune globulin should be used in healthy persons younger
than 12 months of age, immunocompromised persons, persons who have been
diagnosed with chronic liver disease, and persons for whom vaccine is
contraindicated. For healthy persons aged 12 months through 18 years,
hepatitis A vaccine at the age-appropriate dose is preferred to immune
globulin because of the vaccine\'s advantages, including long-term
protection and ease of administration.]{.mark}

[The last paragraph emphasizes the importance of administrating
hepatitis A vaccine simultaneously when IG is used for postexposure
prophylaxis. For persons who receive vaccine, the second dose should be
administered according to the licensed schedule to complete the series.
The efficacy of IG or vaccine when administered later than two weeks
after exposure has not been established.]{.mark}

[Dr. Abramson asked for a motion to approve the VFC resolution. Ms.
Stinchfield so moved and Dr. Baker seconded the motion.]{.mark}

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

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

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

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

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

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

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

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

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

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

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

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

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

[ ]{.mark}

**[Discussion]{.mark}**

[Dr. Amy Middleman from the Society of Adolescent Medicine asked if
TWINRIX was recommended as one of the hepatitis A formulations that can
be used postexposure on travel, even though there are no data. Dr. Bell
clarified that the wording on TWINRIX for the travel recommendation was
unchanged from the previous statement. The antigen content of hepatitis
A in TWINRIX was only available for adults and it is half of that in the
single-antigen vaccine. Since there is no information about the use of
TWINRIX for postexposure prophylaxis, TWINRIX is not included in the
hepatitis A vaccine postexposure prophylaxis recommendation. The VFC
vote is the postexposure vote, not the travel vote, and so it has to do
with hepatitis A vaccine, not TWINRIX. But TWINRIX currently is in the
VFC language for preexposure prophylaxis for hepatitis A for
18-year-olds.]{.mark}

**[[VACCINE FINANCING]{.underline}]{.mark}**

**[Dr. Grace Lee, Harvard Medical School, Boston Children's
Hospital]{.mark}**

**[Dr. Walter Orenstein, Emory Vaccine Center]{.mark}**

**[Dr. Guthrie Birkhead, New York State Department of Health,
NVAC]{.mark}**

[]{.mark}

**[Underinsured Children]{.mark}**

[**Dr. Lee** presented research looking at gaps in vaccine financing for
underinsured children in the U.S. The number of vaccines routinely
recommended for children and adolescents has more than doubled over the
past decades; in 1985 there were vaccines to prevent seven diseases,
whereas now there is protection against 16 infectious diseases. However,
the cost has risen over 20-fold, from about \$45 in 1985 to almost
\$1200 to fully vaccinate a female child in 2006. Many of the newer
vaccines, such as HPV vaccine, rotavirus vaccine, meningococcal vaccine,
and PCV7, are significantly more expensive.]{.mark}

[In the U.S., financial coverage of childhood vaccines depends on
whether or not a child has insurance and if so what type of insurance.
Most private health insurance plans cover the cost of recommended
vaccines, but some privately insured children are underinsured for
vaccines. In those cases, patients either pay out-of-pocket or are
referred to the public sector to receive publicly purchased vaccine from
the state. Even that depends on whether a state has adequate 317 or
state funding available. Publicly insured children (e.g., Medicaid) and
the uninsured receive vaccines free of charge through Vaccines for
Children (VFC).]{.mark}

[The private sector accounts for 46 percent of vaccine purchase. Two
federal funding sources, VFC and 317, account for 43 percent and 6
percent of the total vaccine purchase in the U.S., respectively, and
state funding contributes to about 5 percent.]{.mark}

[VFC is a federal entitlement program linked to ACIP, so when ACIP votes
to include a vaccine the funding must be provided to purchase vaccine
for eligible children, including the uninsured, Medicaid insured,
American Indian or Alaskan natives, and the underinsured, but only if
they are served at a federally qualified health center (FQHC) or a rural
health center (RHC). Unfortunately, there are a limited number of these
centers, so access is not readily available to all. In contrast, 317
funding is a discretionary annual appropriation that can be used for
both children and adults.]{.mark}

[As the number and cost of vaccines increases, VFC funding increases
accordingly. In 2007, nearly \$2 billion will available for vaccine
purchase from VFC funds. However, 317 funding has remained level, which
means additional funding for new vaccines is not available for those who
depend on 317 funding, such as the underinsured.]{.mark}

[After the VFC program came into effect, there were three different
types of state vaccine financing policies: universal, VFC enhanced, and
VFC only. VFC-eligible children can receive vaccine in the public
sector, in the private sector, or in FQHCs or RHCs. Underinsured
children can receive vaccine in the public sector or the private sector.
Fully insured children typically receive vaccine in the private
sector.]{.mark}

[In universal-purchase states, all vaccines recommended by ACIP are
given to all children in all settings. In VFC-enhanced states, all
vaccines are provided to VFC-eligible children and underinsured children
in the public sector and the private sector, but not to insured
children. In VFC-only states, all vaccines are provided to VFC-eligible
children, but underinsured children in the public and private sectors do
not necessarily have access to vaccines unless there happens to be
adequate 317 or state funding available.]{.mark}

[Historically, vaccinating underinsured children was not a problem
because many of the vaccines were inexpensive and there was adequate 317
funding. The gap began to widen in 2000 when the pneumococcal conjugate
vaccine was recommended for use. The addition of PCV7 actually doubled
the cost of immunizing a child. Even though PCV7 was covered by VFC,
many states could not cover it for other children, resulting in the
creation of two new vaccine financing policies: universal select and
VFC-enhanced select. The universal-select and VFC-enhanced-select states
could provide some but not all vaccines to the underinsured, whereas
they could provide all recommended vaccines to VFC-eligible children,
including PCV7.]{.mark}

[The objectives of the two-phase study presented by Dr. Lee were to
describe the variation among states regarding access to new vaccines for
underinsured children and to identify barriers to state implementation
of new vaccines. In the first phase, one-hour qualitative telephone
interviews were conducted with nine state immunization managers from
November to December of 2005. States were chosen to include different
types of vaccine financing policies. Phase 2 was a national survey;
those not previously interviewed were sent written surveys and had
one-hour semi-structured phone interviews. Surveys and interviews
included questions about the status of the implementation of new
vaccines, barriers encountered, and any changes in their vaccine
financing policy.]{.mark}

[The overall response rate was 89 percent; 48 of 50 state grantees
participated in Phases 1 and 2 and two of six city grantees participated
in Phase 2. The immunization program managers had been in their
positions from six months to 27 years, with a median of five years.
Fourteen percent of grantees were considered universal, 12 percent were
universal select, 20 percent were VFC-enhanced, 16 percent VFC-enhanced
select, and 38 percent were VFC only.]{.mark}

[There have been many changes regarding state vaccine financing policies
since 2004. In general, states found that they needed to restrict their
policies further, in part because of the number of new vaccines
approved. Two states went from universal to universal select, five
states went from VFC-enhanced to VFC-enhanced select, and three states
went from VFC-enhanced select to VFC only. Interestingly, one state
temporarily went in the other direction because they were able to secure
state funding to purchase of Prevnar for the underinsured. However, they
expecte to go back to VFC-enhanced select as soon as new vaccines became
available.]{.mark}

[States and cities were asked whether they were able to provide vaccines
to the underinsured in the private sector; 35 percent of underinsured
children could not receive varicella vaccine in the private sector, 50
percent for Prevnar, nearly 70 percent for Menactra, 50 percent for
Tdap, and 56 percent for hepatitis A. Approximately half of underinsured
children could not be vaccinated by their regular provider unless they
could pay out of pocket. These underinsured children would typically be
referred to the public sector.]{.mark}

[When program managers were asked if they were able to provide vaccine
for underinsured children in the public sector, nearly 40 percent of
programs were unable to supply Menactra to those children. Nearly 15
percent were unable to supply Prevnar and hepatitis A, and 4 to 5
percent of the states were unable to supply Tdap or varicella. This is a
significant concern because the public sector has been a safety net for
these vulnerable children. Many public health practitioners voiced
discomfort about turning away children who could not afford to pay for
new vaccines.]{.mark}

[Questions about barriers to implementation in the underinsured
population were directed at states or cities that were not able to
implement these vaccines for all underinsured children. Barriers cited
included limitations on 317 funding and insufficient state funding, by
which they meant they could not secure additional state funds for new
vaccine purchase or, more commonly, their states had no money for any
vaccine purchase.]{.mark}

[Finally, program managers were asked about strategies used to address
limitations in vaccine financing. Twenty-seven states had limited
provider vaccine choice as a way to purchase the least expensive vaccine
and be able to buy more vaccine. Twenty-five states received additional
annual state appropriations to augment their budgets and thirteen states
had expanded the designation of FQHCs or RHCs. Nine of 32 states with
adult vaccination programs had to decrease the amount of adult vaccine
purchased in order to assure enough money to purchase childhood
vaccines. Four were fortunate enough to have had some health-plan
appropriations and one state billed insurance companies for vaccines
given to insured children in the public sector.]{.mark}

[Those 13 states that expanded the designations of FQHCs or RHCs
essentially increased the number of sites where underinsured children
could receive VFC vaccine, which increased the number of underinsured
children considered VFC eligible. Nine states have been able to
designate some public VFC providers as FQHCs or RHCs. Three states have
designated all public VFC providers so that underinsured kids could
receive vaccine anywhere in the public sector and one state was able to
designate all private and public VFC providers as FQHCs or RHCs, so
underinsured children could receive all vaccines in either the public or
the private sectors.]{.mark}

[The study found that the current vaccine financing system was
increasing the gap for underinsured children in the U.S. Given the
estimate of about 14 percent of underinsured children in the U.S., about
3.9 million children are unable to receive Menactra in the private
sector and another 1.1 million underinsured children are unable to
receive Menactra in the public sector. Limitations in 317 and state
funding are clearly contributing to this gap. State immunization program
managers are finding creative solutions to try to address limitations,
but expanded access through funding and/or legislation is needed to
protect this increasingly vulnerable population.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[Dr. Hull asked what the birth cohort size was, to put the number of
children unable to get Menactra in context. Dr Lee replied that there
were usually 4 million children in a U.S. birth cohort. She added that
there was an increasing number of high-deductible health plans or
catastrophic health insurance plans, which do not necessarily cover the
cost of preventive care, so this may increase the proportion of
underinsured.]{.mark}

[Mr. Phil Hosbach of sanofi pasteur commented that the fact that 27
states had limited provider choice was not a new phenomenon; it has
existed since the implementation of the VFC program. From this
manufacturer\'s perspective, it is a public health policy that stifles
competition and innovation. He added that it was useful to know the
number of children not being covered for different vaccines by state,
since they vary in size, scope and socioeconomic status.]{.mark}

[Mr. Beck asked whether the gap could be expressed in terms of dollars.
Dr. Lee replied that the calculation for Menactra would be \$83 times
the 1.1 million children who could not receive vaccine in the public
sector. If one were to consider the 15 percent that were unable to
receive Prevnar or hepatitis A, the total could easily reach \$100
million. Dr. Schuchat added that CDC submitted a report to Congress
about unmet needs in the underinsured and the cost of vaccine purchase
had an estimated dollar figure for vaccines that were not reaching the
underinsured.]{.mark}

[Dr. Schaffner noted that HPV vaccine was not included in this estimate.
Dr. Lee explained that HPV vaccine had just been introduced at the time
of the study and many states had not yet implemented it. This will of
course increase costs. Dr. Schaffner also pointed out that insurance
that does not cover vaccines is not health insurance and that the study
ended at the 19^th^ birthday. Adult vaccination is also a
concern.]{.mark}

[Dr. Temte of the American Academy of Family Physicians commented that
just because private insurers cover vaccine does not mean that private
providers will be fully reimbursed for the cost of vaccine. For those
involved in VFC, there are a lot of regulations around reimbursement and
many private physicians are no longer willing to incur the costs. Dr.
Abramson added that even human papillomavirus vaccine was being
implemented in stages. The fact that VFC is an entitlement does not mean
everybody has the money to implement the full recommendation.]{.mark}

[Dr. Rodewald said that the Office of Management and Budget had provided
sufficient funding to implement VFC for HPV. After 3 or 4 months of HPV
implementation and availability of the contract, all of the state
programs and all of the urban-area grantees had begun the HPV vaccine.
Any limitations would relate to the degree to which a state wants to
launch a catch-up campaign and variation in the amount going to adults.
About a month ago, approximately 5 million doses of the vaccine had been
sold and the VFC program had purchased about 60 percent of those
doses.]{.mark}

[]{.mark}

**[AMA/AAP Immunization Congress]{.mark}**

[**Dr. Orenstein** shared information from an Immunization Congress
sponsored by the American Academy of Pediatrics and the American Medical
Association, which focused on concerns about the need to remove
financial barriers to access, particularly for newly recommended
vaccines. The first day was devoted to financing of vaccines recommended
for children, within existing legislation as well as potential new
legislation. Attendees included private providers, medical societies,
public health societies, insurers, employers, manufacturers, and
representatives from government at the federal, state, and local level.
Nine recommendations were made, which have been under consideration by
the National Vaccine Advisory Committee Vaccine Financing Working
Group.]{.mark}

[There was consensus on a number of points. Stakeholders supported
universal access to all ACIP-recommended vaccines without financial
barriers, although it was recognized that just removing financial
barriers was not sufficient to ensure high immunization coverage. The
private and public sector collaboration in vaccine delivery should be
maintained. Through the VFC and other efforts, an army of private
providers has been enlisted to decrease vaccine-preventable diseases by
immunization. The medical home can add more medical benefits to children
than vaccines alone, so vaccination of children by private providers
ought to be supported. The best way to assure continued private-sector
participation is to assure some reasonable return on that investment
beyond costs.]{.mark}

[There was consensus that vaccines are different from most other
preventive measures. Vaccinees receive direct protection, but because
the vast majority of vaccine-preventable diseases are spread
person-to-person, vaccination also indirectly protects other members of
society. Solutions need to solve problems in every state, otherwise some
states may become reservoirs for disseminating diseases to other states.
Problems include under-insurance, inadequate or non-timely
reimbursement, costs for vaccine ordering, storage, handling and
paperwork, and the actual administration of vaccines. Unfairness of
Medicaid reimbursement for administration was another big concern, with
a range from \$2 to more than \$18.]{.mark}

[The first working group recommendation was to work with federally
qualified health centers and rural health clinics to delegate authority
to public health clinics to serve underinsured children through the
Vaccines For Children program. This decreases the pressure on the need
for increased 317 appropriations and moves children from discretionary
funds to entitlement funds. It also offers a safety net for referring
underinsured children to public clinics for vaccines if other solutions
to underinsurance are not found. All stakeholders represented at the
meeting supported this effort, including manufacturers, provided it did
not decrease the private sector market. Recent data from the Association
of State and Territorial Health Officials indicate that 22 of the 64
immunization grantees have now implemented this delegation authority,
including sixteen states, four urban areas, and two territories.]{.mark}

[The second recommendation was to obtain as soon as possible the actual
cost of delivering vaccines in private practice settings, using
gold-standard methods so that all stakeholders, including CMS, business
groups and insurers, could accept the information as valid. Input from
these stakeholders should be obtained prior to initiating the study and
the AAP and AAFP could use that data to educate insurers and advocate
for better reimbursement rates. Providers indicated that their
number-one concern was inadequate administration fees, not vaccine fees.
They also felt that the medical societies should advocate with insurers
to have contracts that covered changes in mid contract, such as vaccine
price increases or new vaccines added to the schedule.]{.mark}

[A third recommendation was that the medical societies should work with
manufacturers and distributors to obtain more favorable terms for
payments for vaccine inventories. This is a major cash outlay,
especially for smaller practices and for new vaccines. Solving this
issue should be in the interest of the manufacturers and, if necessary,
could be built into pricing.]{.mark}

[A fourth recommendation was that medical societies work with the AMA to
better define all of the components that go into CPT codes for vaccine
and vaccine administration.]{.mark}

[A fifth recommendation was that the National Vaccine Advisory Committee
Vaccine Financing Working Group examine the potential role of tax
credits for insurers and/or employers in eliminating underinsurance. The
group felt there were not yet enough details to endorse such a
recommendation, but it could be a positive incentive.]{.mark}

[A sixth recommendation was to convene a working group of key
stakeholders, including manufacturers, to determine whether some form of
universal federal vaccine purchase or funding should be pursued. This
option has been vigorously opposed by the vaccine industry in the past,
but it might be designed in such a way as to gain their support.]{.mark}

[The seventh recommendation was that the societies should obtain data
from the Centers for Medicare and Medicaid Services that led to the
current influenza administration fee and use that data to advocate at
the state level for enhanced Medicaid reimbursement. There has not been
sufficient publicity given to the tremendous variation in Medicaid
reimbursement rates for administration, and the data from Recommendation
2 should be used to advocate for higher rates.]{.mark}

[Recommendation 8 dealt with the cost of obtaining and administering
combination vaccines, compared to individual vaccines. If they are shown
to be more costly, there should be better reimbursement for combination
vaccines.]{.mark}

[The last recommendation was that the American Academy of Pediatrics and
the American Academy of Family Physicians should collect data on best
business practices to minimize vaccine and vaccination costs and
disseminate them to their members.]{.mark}

[]{.mark}

**[NVAC Financing Working Group]{.mark}**

[**Dr. Birkhead** presented an update from the National Vaccine Advisory
Committee Vaccine Financing Working Group. New vaccines added to the
schedule and new recommendations have created a crisis in the delivery
system. However, the problem is not readily visible because there has
been no resurgence of vaccine-preventable diseases due to failure to
vaccinate and morbidity from the diseases prevented by the new vaccines
may not yet be recognized as a problem.]{.mark}

[NVAC has a long history of looking at vaccine finance issues. In
2006-2007, a working group was charged with obtaining information from
stakeholders on the challenges in creating optimal approaches to vaccine
financing in both the public and private sectors and their impact on
access; establishing a process for selecting and addressing two to three
topics per year; developing specific targeted policy options in these
areas; and presenting the findings and policy options to the full NVAC
for discussion. Members of the working group included a number of NVAC
members, as well as representatives from insurance, pharmaceuticals and
academia.]{.mark}

[The primary focus in the first year was childhood immunization. In the
public sector, although vaccine is available through the Vaccines For
Children program, administration fees are a problem. The Medicaid
administration fee is very inadequate and the base rate has not been
updated since 1994. Uninsured children are eligible for VFC vaccine, but
there is no mechanism to supply an administration fee. However,
providers who participate in VFC cannot turn anyone away for inability
to pay. The 317 program has not kept pace with the new vaccines that
have come along.]{.mark}

[In the private sector, providers are stressed in terms of the cost of
maintaining an inventory. It becomes a cash-flow problem, along with
loss of vaccines due to power failure or other reasons. There are
concerns on the insurance side about the adequacy of reimbursement for
vaccine costs and/or administration costs.]{.mark}

[The working group obtained input from the various other NVAC
subcommittees and stakeholders and commissioned a number of surveys to
obtain data on the actual impact at the practice level. There are also
other studies of cost of vaccination in process. Members of the working
group attended the AMA-AAP vaccine financing congress. CMS is
represented on the working group, and has helped the group understand
the current system of Medicaid and Medicare reimbursement for
vaccination. Individual vaccine manufacturers will be interviewed to
gain their perspective, and something similar is planned for
insurers.]{.mark}

[Dr. Birkhead reported on two studies commissioned by the working group.
The first was an assessment of charges and reimbursement for vaccines
and administration fees in private practices. The purpose was to
determine the range of prices paid for childhood and adolescent
vaccines, the administration fees charged, and the reimbursement paid by
three large insurers. Thirty practice managers were surveyed by
telephone, from five non-universal purchase states, medium, small, and
large, with metropolitan and non-metropolitan areas. Results are
expected in the fall.]{.mark}

[The second study looked at private provider attitudes regarding vaccine
financing and to what extent they influence their willingness to adopt
new vaccines. This is a cross-sectional survey through the mail of a
random sample from the AMA master file. Results are anticipated by the
fall as well.]{.mark}

[Meanwhile, work has begun on a draft of a white paper laying out the
issues and making some recommendations. There is overall agreement on
the goal: to ensure universal access to all vaccines recommended by ACIP
for children and adolescents without financial barriers, and there are a
number of conclusions. One is that the current public and private sector
mixed-financing system for purchase of pediatric and adolescent vaccines
has the capacity to deliver the currently recommended vaccines but it
may not assure access to all children and adolescents without financial
barriers. Financial incentives can play a major role in strengthening
the system to deliver current as well as future recommended
vaccines.]{.mark}

[There appear to be wide variations in vaccine costs and reimbursements
to providers. It is not clear that CPT codes take into account such
factors as the need to enter data in the vaccine registries, time for
parental counseling and discussion, maintaining reminder systems, and
insurance policies against catastrophic loss of vaccine.]{.mark}

[The group felt that HRSA and CDC should encourage federally qualified
health centers and rural health clinics to work with their local public
health departments to serve underinsured kids who cannot be served at
the federally qualified health centers because of lack of access or
availability. The Association of State and Territorial Health Officials
is already working with states around this point.]{.mark}

[The maximum allowable reimbursement rates for administration in the
Medicaid program should be re-examined. Once those rates are set, states
need to contribute maximally to the vaccine administration fee and then
draw down federal dollars to create the full administration fee. CDC
should collect data on actual non-vaccine costs of vaccinating in
private practices, using a method that is accepted by the major
stakeholders and passes muster with CMS and insurers, so that it can
potentially form the basis of the new administration fee
amounts.]{.mark}

[Medical and other relevant societies should work with the AMA to be
sure that the CPT codes used for billing contain all necessary elements.
Medical societies should collect data on best-business practices to help
practices design their work load.]{.mark}

[Vaccines may be recommended by ACIP in the middle of an insurance
policy cycle, and so provider and insurance contracts should allow for
increases in new vaccines or increases in existing vaccines mid
contract. Vaccine manufacturers and third-party distributors should work
with providers to reduce financial liability for initial inventories of
new vaccine. There should be a mechanism to increase Section 317 funding
when new vaccines become available and mechanisms to utilize the 317
funding to support administration fees.]{.mark}

[NVPO should convene key stakeholders, including manufacturers and
insurers, to talk about these issues in light of data from the surveys
and other studies. The idea is to look outside the box and find
solutions that would be mutually agreeable to all parties. For example,
is there a way to design a federal vaccine universal purchase that has
not been thought about yet, perhaps around a voucher system?]{.mark}

[Regarding next steps, the practice and cost survey along with the draft
white paper will be submitted to NVAC for consideration and potential
adoption. Discussions will continue around the administration fees and
Medicaid, to either increase those or improve state participation.
Another option is to look at the Medicare influenza administration rate
and see if that can be adopted in the Medicaid setting. Vaccine economic
evaluation projects are encouraged. Finally, there will be a
stakeholders meeting in the winter or early next year.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Lett asked whether anyone had thought about how to identify and
address the ERISA problem. Dr. Birkhead replied that it had come up in
the beginning. Self-Insured plans or ERISA plans are not regulated
through state insurance departments, so it is more of a third-rail
issue. Dr. Orenstein added that there has been legislation in the past
that offered to open up ERISA, but it never went anywhere. It would be
important to know how big the underinsured problem actually is. Old IOM
estimates ranged from about 5 percent of the birth cohort up to about 13
or 14 percent. More recent data indicate about 7 percent.]{.mark}

[Dr. Rodewald commented that vaccines and vaccine coverage constitute a
relatively small proportion of the total healthcare cost, so point
estimates are difficult to obtain. They are not included in most surveys
of insurance coverage. However, the point estimates from the IOM seemed
to hover somewhere around 10 to 11 percent. The National Immunization
Survey has added an insurance module that will include adolescents and
help obtain underinsurance information. The 2001-2002 module was in the
10 to 11 percent range as well.]{.mark}

[Dr. Freed, as chair of NVAC, emphasized that this was all only draft
language, which has not been approved by the working group. Once the
full NVAC receives the recommendations from the working group, there
will be a process of deliberation, which includes comments from federal
agencies, the public, and the members themselves. NVAC has no statutory
authority to enforce its recommendations; its role is to make specific
recommendations to the Assistant Secretary for Health and stimulate
public debate. Then people can use those recommendations in their own
way.]{.mark}

[Dr. Abramson asked if there was any sense about what the Undersecretary
of Health might do. Dr. Gellin replied that the Assistant Secretary for
Health was following the progress of this working group and got regular
reports, so the good news was that people are listening to the
debate.]{.mark}

**[[PROPOSED REVISIONS TO THE ADULT IMMUNIZATION
SCHEDULE]{.underline}]{.mark}**

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

**[Gina Mootrey, CDC/NCIRD, ISD]{.mark}**

[]{.mark}

[**Dr. Morse** explained that the work group's initial task was to add
zoster to the adult schedule, but then members asked how they could
actually promote and increase immunizations in this population and make
the adult schedule more user friendly and consistent with the childhood
and adolescent schedule. Potential future activities include revising
healthcare worker recommendations and having focus groups review the
Medical and Other Indications schedule. The hope is to publish this
recommended adult immunization schedule in October 2007, which would
correspond with a number of activities to promote adult vaccines, then
incorporate the adult immunization recommendations into the next general
recommendations for simplification, and eventually look at the adult
immunization schedule for HIV-infected persons.]{.mark}

[]{.mark}

[**Dr. Mootrey** went over the changes made to the schedules and the
footnotes. The proposed age-based schedule for 2007 and 2008 was
presented. The bar for HPV vaccine has been shortened to show that it
only goes through age 26. The bar for varicella vaccine is now yellow
throughout. The previous one had yellow for 19 to 49 years and purple
for 50 to 64 years, pending zoster recommendations. The zoster vaccine
bar is yellow for those 60 years and older. The yellow bar wording has
been changed from "age requirements *and* lack of evidence of immunity"
to an \"*and/or*,\" so that this schedule would apply if one had age
requirements and/or lack of evidence of immunity. Wording has been added
giving a reference to the ACIP recommendations and the extent of
available data. The URLs for the ACIP recommendations were updated and a
note was added that meningococcal vaccine is covered by the injury
compensation program.]{.mark}

[Dr. Mootrey then presented the proposed revisions to the Medical and
Other Indications schedule 2007 and 2008. The working group is proposing
a revision to the title of this table, to indicate that the vaccines
mentioned do not all have a specific recommendation, but that there is
no contraindication and they may be given for these different groups.
Mention is made that meningococcal vaccine is covered by the Vaccine
Injury Compensation Program. The column for the immunocompromising
conditions has been shortened and a footnote added because of the
increasing number of conditions. To make things simpler, the
immunocompromising conditions column is now adjacent to the HIV column.
Because of indications for several of the vaccines, specifically
varicella and MMR, the HIV column was split, based on CD4 count.]{.mark}

[The chronic liver disease column used to have recipients of clotting
factor concentrates as a risk group. Since that now only applies to
hepatitis A vaccine, it has been taken out of the column heading but
remains in the footnote for hepatitis A vaccine.]{.mark}

[For influenza vaccine, there is now a specific indication that TIV or
LAIV can be given to healthcare workers, and there is now a yellow bar
as opposed to a purple bar for the asplenia column. For meningococcal
vaccine, the table indicates that one or more doses could be given,
depending on various risk indications.]{.mark}

[Zoster vaccine was added, with a contraindication for pregnancy,
immuno-compromising conditions, and HIV CD4 count less than 200.
However, Dr. Mootrey said she had just attended a meeting of the
DHHS-IDSA work group on revising the guidelines for prevention and
treatment of opportunistic infections in HIV-infected persons, where it
was felt that it would not be appropriate to indicate any kind of
recommendation for zoster vaccine in HIV-infected individuals,
regardless of CD4 count, since there are no data on safety,
immunogenicity or efficacy in those individuals. There will be data in
about a year from an ongoing study. Currently there is a yellow bar for
other risk groups, but Dr. Mootrey proposed leaving that portion blank
until there could be further discussion.]{.mark}

[There were some general changes to enhance the footnotes, based on the
harmonized-schedule discussion last year. There is a lot of explanatory
language in these footnotes, particularly to describe the indications
for use of vaccine. Contraindications are noted by the red bars on the
schedule. Several of the vaccine footnotes contained language about
contraindications during pregnancy, and that language was removed for
those vaccines. For each of the footnotes, a URL has been added that
links directly to the vaccine-specific ACIP statement.]{.mark}

[The Tdap footnote has been revised to highlight the general statement
regarding replacing only one Td with Tdap, just by reordering the
footnote wording. The pregnancy language in HPV was taken out and
language was added to indicate that HPV vaccine is not specifically
indicated, based on the medical conditions mentioned in the Medical and
Other Indications table.]{.mark}

[At the opportunistic infection meeting mentioned earlier, the group did
not want to give the impression that HPV vaccine was actually
recommended for HIV-infected adults, even though it is not
contraindicated. The footnote in the schedule also indicates that
efficacy and the immunogenicity may be lower in certain persons. The new
language for HPV says, *\"HPV vaccination is not specifically
recommended for females with medical indications described in the table
\'Recommended Adult Immunization Schedule by Vaccines That May Be
Indicated for Adults Based on Medical and Other Indications.\'*
*Although, because it is not a live virus vaccine, it can be
administered. However, the immune response and vaccine efficacy might be
less than that in persons who are immunocompetent or who do not have the
described medical indications.\"*]{.mark}

[MMR also had the contraindications language for pregnancy, and that has
been removed.]{.mark}

[The varicella footnote has been revised to indicate the use of
single-antigen varicella vaccine. A phrase regarding an epidemiologic
link to a laboratory-confirmed case has been added as a requirement for
evidence of immunity in a healthcare-provider diagnosis of a mild or
atypical case, and pregnancy language has been removed.]{.mark}

[For pneumococcal vaccine, to be consistent with the Medical and Other
Indications schedule heading, chronic alcoholism and chronic
cardiovascular disease have been added to the text. CSF leaks was
deleted from the immunodeficiency column and added to the footnote text.
In the footnote for revaccination with pneumococcal vaccine, the listing
of the multiple immunodeficiency conditions has been deleted.]{.mark}

[For hepatitis A vaccine, the schedules for the two single-antigen
vaccines have been clarified. Single-antigen formulations should be
administered in a two-dose schedule, and the specific vaccine based on
which schedule was being used has been added. For hepatitis B, persons
who receive clotting factor was removed as a risk group. For
meningococcal vaccine, the footnote now clarifies that persons who
remain at increased risk as opposed to high risk for infection may be
indicated for revaccination.]{.mark}

[A new footnote has been added for herpes zoster vaccine stating that
the vaccine is recommended. *\"A single dose of zoster vaccine is
recommended for adults 60 years and older whether or not they report a
history of herpes zoster and persons with chronic medical conditions may
be vaccinated unless the contraindication or precautions exist for their
condition."* In the next iteration, more wording may be added.]{.mark}

[A new footnote was added to address the growing list of
immunocompromising conditions. It says that inactivated vaccines are
generally acceptable and live vaccines are generally avoided when there
are immune deficiencies or immune-suppressive conditions. For guidance
relating to specific conditions, refer to the general recommendations,
giving the URL and the specific pages and the table that describes
immunocompromising conditions.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Gilsdorf said that the inclusion of \"recommended\" leaves the
impression that everything in the yellow bar is a recommendation for the
use of these vaccines, but for chronic disease indications, HPV and
Zostavax are not recommended. She suggested adding a different color or
texture to those yellow bars that indicate that it is acceptable to use
it, but not specifically recommended. Dr. Baker added that if that were
done, one would have recommend Tdap in pregnancy, which the ACIP does
not do.]{.mark}

[Dr. Hull asked if people over 60 should get zoster vaccine rather than
varicella. Dr. Mootrey replied that they would not if they have never
had varicella. Dr. Hull added that the footnote on the yellow bars on
both tables should be re-examined regarding the addition of \"or.\" For
example, one would not recommend zoster for healthcare workers younger
than 60.]{.mark}

[Dr. Neuzil expressed confusion about the bars for HIV and zoster or
HPV, since they did not seem to reflect existing ACIP recommendations.
Dr. Mootrey explained that the new language for HPV was consistent with
ACIP recommendations because, for HIV-infected individuals, it is
neither recommended nor contraindicated. Zoster vaccine is not
specifically recommended, but it may be considered. Dr. Neuzil
recommended pulling out the zoster statement if there had been no
specific discussion on CD4 count and HIV.]{.mark}

[Dr. Schuchat thought that when ACIP considered the zoster statement,
HIV studies were ongoing. Although there is a lot of interest among the
HIV providers and patients in getting this vaccine, more information
will be forthcoming and perhaps ACIP should wait to make a full
statement. A second issue was an inconsistency in the varicella
upper-age group. Providers might be confused whether to give varicella
or zoster or both if the patient is 65. One of the footnotes talks about
evidence of immunity to varicella being 'born before 1980', so that it
would not make sense to have this upper-age group.]{.mark}

[Dr. Treanor thought that the issue about whether to screen people for
evidence of prior immunity to varicella before giving them zoster
vaccine had come up and the committee had decided that that was not
necessary. But if it was known that someone was not immune, they should
receive varicella vaccine. In another discussion, since there is only a
small number of HIV-infected individuals who are 60, the issue was not
so much the recommendation but whether it will be considered a
contraindication. He also recalled a discussion of the fact that
varicella vaccine is relatively safe in individuals who are
immunosuppressed, including those with advanced HIV, and that HIV with a
CD4 count of over 200 is not a contraindication in the FDA
label.]{.mark}

[Dr. Pickering observed that the recommendation for MMR says it can be
given to HIV-infected children with CD4-positive counts above 15
percent. Varicella can be given to that same group, but MMRV is not
recommended. The zoster vaccine has 14 or 15 times the amount of
varicella, and a recommendation with no data is worrisome. Dr. Treanor
added that this was a vaccine being administered to people who were
already immune to the vaccine virus.]{.mark}

[]{.mark}

**[Vote]{.mark}**

[Dr. Abramson asked whether the committee was comfortable voting on the
recommended schedule, given that the comments and suggestions would be
dealt with.]{.mark}

[Dr. Hull moved to accept, realizing there would be minor modifications
per the discussion. Mr. Beck seconded the motion.]{.mark}

[]{.mark}

[Dr. Lieu : yes.]{.mark}

[Dr. Morita : yes.]{.mark}

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

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

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

[]{.mark}(Dr. Abramson noted that clarification was needed whether Dr.
Treanor could vote. Dr. Pickering said he would find out and correct the
minutes accordingly.)

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

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

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

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

[Mr. Beck yes.]{.mark}

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

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

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

**[[PROPOSED REVISIONS TO THE CHILDHOOD-ADOLESCENT SCHEDULE FOR
2008]{.underline}]{.mark}**

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

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

[]{.mark}

[**Dr. Calugar**'s presentation was for information and discussion only,
since it is still a work in progress. She showed the current recommended
immunization schedule for ages zero through six years and the one for 7
to 18 years, as well as for catch up. The format was based on
focus-group discussions conducted last year. Feedback on the current
format for 2007 came from participants at the National Immunization
Conference and the NIP info hotline of the CDC. Providers say it is
easier to read, convenient to print, and useful to separate age groups.
The colors are harmonized with the adult schedule, however the green
catch-up bars were said to be confusing. The immunization providers
claimed that the content of the Childhood-Adolescent Schedule for 2007
is clearer, the footnotes are useful and it has the correct level of
detail in comparison with prior schedules.]{.mark}

[Suggestions on how to improve the schedule were related to the
hepatitis B vaccine birth dose, and clarifications for PCV indication,
for the zero-to-six schedule and catch-up. More details for children
with special medical conditions would be helpful. Options for
black-and-white copies would also be very useful, as would the use of
brand names, which is normally avoided as much as possible.]{.mark}

[The work group analyzed the accumulated information and conducted a
joint meeting with the adult immunization schedule work group, which has
experience with the best approaches for persons with special medical
conditions. After a discussion about synchronizing the timing of the two
schedules, it was decided to adhere to the existing time lines, i.e.,
the adult group will publish in October, and the childhood group will
present final drafts in October for the ACIP vote and publish in January
next year. Discussing and providing feedback for a draft immunization
schedule for HIV-infected children ages zero to six years was another
activity reported by the ACIP Childhood-Adolescent Schedule
workgroup.]{.mark}

[The process of updating the current schedule took into account other
new vaccines that had been approved or were being considered by FDA.
Sometimes there are new indications for existing vaccines, such as a
potential recommendation for a younger age group for FluMist vaccine
starting with the 2007/2008 influenza season (pending FDA
decision).]{.mark}

[Dr. Calugar showed the current schedule for ages zero to six years and
pointed out that there were yellow bars for recommended ages, green for
catch-up immunization, and purple for certain high-risk groups. Since
providers find the green bars confusing and redundant, the hepatitis B
series and Hib vaccine green bars will be removed.]{.mark}

[Dr. Calugar then showed the current schedule for ages 7 through 18
years. ACIP will be voting on an updated recommendation for Menactra
vaccine (MCV4), which would change the indications on the schedule.
Previously it was presented as a yellow bar for a range of recommended
ages up to 11 or 12, then for certain high-risk groups and yellow for
15-year-olds. Now there will a green bar in the catch-up immunization
schedule for ages 13 through 18, which will make MCV4 consistent with
the other two adolescent vaccines \-- Tdap and HPV series.]{.mark}

[The current catch-up schedule is divided, with ages four months through
six years at the top and ages 7 through 18 years at the bottom. In all
current schedules, the footnotes are bulleted. The minimum age for
administration is on the first line for each vaccine, and the updated
references are included.]{.mark}

[In the footnotes for age groups zero through six years, the work group
proposes adding*, \"For additional details, see catch-up immunization
schedule.\" *]{.mark}

[Regarding the wording for the hepatitis B birth dose, if the mother is
HBsAG negative, the birth dose can be delayed in rare cases with a
physician\'s order and a copy of the mother\'s negative HBsAG laboratory
report in the infant's medical record.]{.mark}

[The third and the last change proposed is for pneumococcal conjugate
vaccine wording. *\"Administer PCV at ages 24 to 59 months in certain
high-risk groups*,\" and then add, \"*Consider catch-up for other
children aged 24 through 59 months*.\"]{.mark}

[The proposed changes to the footnotes for the age group 7 through 18
years were simple. The group suggested adding a statement saying,
*\"Catch-up bars highlight the importance of the adolescent platform.
For additional details, see catch-up immunization schedule.\" *]{.mark}

[For the catch-up schedule, the PCV wording will be updated.
\"*Administer PCV at ages 24 to 59 months in certain high-risk groups.
Consider catch-up for other children aged 24 to 59 months.\"* And then,
as stated, *\"Vaccine is not generally recommended for children aged
older than five years.\" *]{.mark}

[Updating the immunization schedules requires multiple activities, and
the work group recognizes the importance of the feedback from
immunization providers, collaboration with different ACIP work group and
subject-matter experts, and harmonization with the stakeholders and the
childhood and adolescent schedule.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Ms. Stinchfield asked to change the wording in the footnotes regarding
the hepatitis B dose from "physician order" to \"provider order,\"
because many people write orders in birth centers.]{.mark}

[Dr. Whitley-Williams, National Medical Association, was confused about
whether children who received the meningococcal conjugate vaccine at 11
to 12 years should be revaccinated five to seven years later when
entering a dormitory in college. Dr. Messonnier responded that the
current thinking was that the duration of protection would be long
enough, and the ACIP recommendations for the MVC4 were based on that
assumption. However, that will continue to be monitored.]{.mark}

[Dr. Abramson said he understood from David Salisbury that the only
problems noted in England have been in those who were immunized before
one year of age and that they have not seen breakthrough cases in the
other age groups to date. Dr. Messonnier said the U.K. vaccines were
mening C conjugate vaccines and each of these vaccines is slightly
different. However, based on the U.K. experience, one would anticipate
that children vaccinated at age 11 would still be protected as they get
to college. In the U.K., studies carried out before they began
vaccinating suggested that children would be protected because they had
memory, but the U.K. data suggest that, at least in infants, memory is
not sufficient to provide protection without a booster dose.]{.mark}

[Dr. Abramson commented that this also relates to the issue of
reimmunization, which needs to be consistent on both the adult and
adolescent schedules.]{.mark}

[Dr. Wexler, Immunization Action Coalition, was concerned about the
catch-up language for PCV, which says to administer PCV at ages 24 to 59
months of age in certain high-risk groups. That language is left over
from the original ACIP recommendations in 2001, where the high-risk
groups who were 24 to 59 months old were not covered by the 2-, 4-, 6-,
and 12-month recommendations. They were written to catch the older kids
in high-risk groups so they wouldn\'t [not]{.underline} get vaccinated.
She wondered why there was still a need to talk about certain high-risk
groups, when these children should have already been vaccinated at 2, 4,
6, and 12 to 15 months. Basically, the wording should say that all
children should be caught up, up to age five. Dr. Calugar replied that
this was consistent with the last ACIP recommendation on PCV. There are
always a few children being seen for the first time, such as an adopted
child, so there has to be catch-up guidance for providers. The aim was
to have only routine recommendations in the schedule and then refer
everyone to the catch-up schedule.]{.mark}

[Dr. Wallace reminded the group that when PCV was first recommended, the
language about catch-up in those older than two was softened, but right
now it does reflect the recommendation. Dr. Lett felt it would be
important to standardize these recommendations for revaccination and
catch-up between the adult and the childhood schedule. Moving back to
meningococcal, she said she recalled that the revaccination statement
excluded those living in dormitories.]{.mark}

[Dr. Decker reported that as far as he knew there were no definitive
data anywhere in the world on the duration of protection from any
conjugate meningococcal vaccine. From clinical trials, there are some
published data showing the lead and rechallenge of children who were
immunized at two to three years of age and children four to five years
of age. They still had significant elevations of antibody, and they
responded briskly and with large rises to challenge. The U.K. had a
problem with breakthrough cases in young children who were vaccinated on
a 2-3-4 schedule, suggesting, perhaps, a problem with that schedule and
the need for a booster. In contrast, the Netherlands implemented a
nationwide 0- to 19-catch-up program and routine immunization at 14
months of age, and they have had no breakthrough cases in anyone
vaccinated in six years. They are not going to give any boosters until
they see epidemiologic evidence of a need to do so.]{.mark}

[Dr. Schuchat pointed out that the apparent inconsistency between the
childhood and adult recommendation was not an inconsistency. The
revaccination comments in the adult recommendation were for those who
receive meningococcal polysaccharide, and those are high-risk adults,
e.g., asplenic or working in labs. Dr. Abramson added that he had asked
for clarification whether it was the polysaccharide followed by the
conjugate.]{.mark}

[Dr. Baker noted that Menactra was licensed on a correlate of immunity,
and that she understood that postlicensure a cohort of adolescents and
young adults would be followed for duration of serologic protective
correlate.]{.mark}

**[[CDC IMMUNIZATION SAFETY OFFICE UPDATE]{.underline}]{.mark}**

**[Karen Broder, CDC/ISO]{.mark}**

[]{.mark}

[**Dr. Broder** provided an overview of the Immunization Safety Office
(ISO) program, described the proposed ISO research agenda development
plans, and presented some preliminary key research themes identified
during an ISO external scientific consultancy meeting. The mission of
the ISO is to assess the safety of vaccines received by children,
adolescents, and adults. It works closely with partners nationally and
internationally to develop, provide, and support high-quality research
in the field of vaccine safety in order to identify adverse events after
vaccination and to assess causality and risk factors. In addition, it
strives to communicate its work in a clear and transparent manner and to
develop scientific methodology and standardize case definitions for
vaccine adverse events.]{.mark}

[Four main research and surveillance components work together to
accomplish this mission. VAERS is an early-warning, national, passive
surveillance system. It identifies vaccine safety signals of potential
concern and generates hypotheses. The Vaccine Safety Datalink project or
VSD is a collaboration between CDC and eight managed care organizations
with comprehensive medical and immunization histories of about 5.5
million people per year. VSD tests hypotheses suggested by signals or
expert review and also conducts vaccine safety surveillance. The
Clinical Immunization Safety Assessment (CISA) network is a
collaboration between CDC and six academic centers with vaccine
subject-matter experts. CISA strives to study the pathophysiology of
adverse events following immunization and identify risk factors,
including host risk factors associated with adverse events, and also
develops evidence-based guidance for clinicians around vaccine safety
issues. The global Brighton Collaboration standardizes case definitions
and provides a common vocabulary for vaccine safety research and
surveillance. ISO also collaborates on a daily basis with other CDC
programs and the FDA.]{.mark}

[In October 2006, ISO conducted an internal peer review to determine
whether the program activities were achieving the mission and identify
areas for improvement. Preliminary conclusions were that ISO should
strive for transparency, clearly identifiable research priorities,
scientific credibility, enhancement of existing collaborations, and
identification of new partnerships. In addition, the office needs to
ensure that it can perform core public health functions under both
routine and emergency situations. Peer reviewers recommended that the
development of the ISO research agenda should include input from
stakeholders in immunization safety and an external review.]{.mark}

[In February 2005, the Institute of Medicine released a report titled
\"Vaccine Safety Research, Data Access, and Public Trust,\" which
recommended that a subcommittee of the National Vaccine Advisory
Committee (NVAC) review and provide advice on the Vaccine Safety
Datalink research plan. In response, the Immunization Safety Office is
developing a comprehensive, scientifically robust research agenda with
extensive internal and external input, in three phases over a three- to
five-year horizon.]{.mark}

[In the first phase, CDC is already developing a draft ISO research
agenda. In the second phase, the National Vaccine Advisory Committee
will facilitate a scientific review of the draft ISO research agenda and
provide advice, and in the third phase, CDC will respond to the feedback
from the NVAC process and finalize the ISO research agenda.]{.mark}

[CDC, the National Vaccine Program office (NVPO), and NVAC are currently
discussing the approach for the Phase 2 NVAC scientific review, and
plans have not been finalized. It is anticipated that this review would
include a broad group of stakeholders in immunization safety as
recommended by the Institute of Medicine.]{.mark}

[To develop this draft ISO research agenda, ISO conducted an external
scientific consultancy and also plans to obtain input from CDC programs
outside ISO, other HHS agencies, the Department of Defense, and various
nonfederal partners. Input from ACIP members will be welcomed through
the CDC-ACIP working-group liaisons.]{.mark}

[The charge to the individual external scientific consultants was to
identify emerging vaccine safety research questions not currently being
addressed, propose potential approaches to study each question, and
advise on prioritization of research topics. Seven consultants were
invited, representing the fields of pediatric infectious diseases, adult
infectious diseases, OB/GYN, immunology, genomics, and epidemiology. In
addition, there were liaison representatives from Federal agencies,
advisory committees, CDC research collaborations, and the ISO, as well
as the Office of the Chief Science Officer, CDC.]{.mark}

[The framework used to guide brainstorming discussions was the five life
stages: infants, children, non-pregnant adolescents, non-pregnant
adults, and pregnant women. Cross-cutting categories included the role
of public perception in shaping the ISO research agenda, considerations
for vaccine safety surveillance, safety of non-antigen vaccine
constituents and new vaccine technologies, and adverse events that occur
years after vaccination. Six consultants also presented their own
perceptions of the most important vaccine safety topics.]{.mark}

[During the brainstorming sessions, consultants thought broadly about
vaccine safety research without considering infrastructure or programs.
Some of the topics that emerged are already being addressed in a current
research activity, or might be more appropriate for other CDC or HHS
programs, for example, studies of risk perception around
vaccination.]{.mark}

[The ISO is compiling a report that summarizes the full spectrum of the
independent advice that consultants provided, but there were some key
themes that appeared most relevant to the future ISO safety research
agenda. One was the need to better understand the relationship between
certain host risk factors and vaccine adverse events. These factors
include prematurity and low birth weight infants; the influence of
gender on vaccine adverse events; pregnancy; aging; the presence of
chronic conditions, including diabetes; as well as genetic
factors.]{.mark}

[Another key area was vaccine-specific safety. In the case of rotavirus
and LAIV, the concern was for a specific adverse event: intussusception
for rotavirus vaccine and wheezing after LAIV. But influenza vaccine was
of general interest because of the need for pandemic influenza
preparedness. HPV was highlighted for a variety of reasons, including
public sensitivities about giving the vaccine to adolescent girls
widely. Tdap and zoster were listed, in part, because of safety issues
regarding off-label use outside the licensed age range.]{.mark}

[Other specific reported vaccine adverse events were included for
different reasons. Some, like intussusception, are of concern following
a particular vaccine (rotavirus), whereas Guillain-Barré syndrome and
demyelinating disorders are of general interest. In addition, with
increasing focus on adult vaccination, consultants identified a need to
understand the incidence of cardiovascular disorders.]{.mark}

[Of the other research topics that emerged during the meeting, some are
relevant to the ISO research agenda, and some may also be relevant to
other research agendas. Topics included the role of novel vaccine
adjuvants, which is coming up in an HPV vaccine currently in the
pipeline; understanding immune mechanisms for vaccine adverse events;
and strengthening surveillance for reported vaccine adverse events,
including signal detection. Understanding age-specific baseline rates of
conditions reported as adverse events was a high priority. Off-label use
of vaccines was another important area, for example, use of LAIV in
persons with conditions that place them at increased risk for influenza
complications.]{.mark}

[Next steps are to work with the individual consultants to complete the
consultancy report, gather input from the other vaccine safety partners,
and develop a draft ISO research agenda that can be shared with NVPO and
NVAC for the scientific review.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[Dr. Treanor asked whether there had been any interest in exploring the
genetic basis of vaccine side effects. Dr. Broder replied that it is
such a new area in vaccine adverse event research that detailed
discussion was outside the realm of this particular consultancy. Dr.
Iskander said his office had been funded by NVPO to conduct a separate
meeting on this general topic, recognizing the emergence of data and
interest. They will be seeking collaboration and input and hope to have
the meeting early in the first quarter of 2008.]{.mark}

[Dr. Katz asked why NIH was not in the list of federal agencies with
liaison representatives to the ISO external scientific consultancy. Dr.
Broder replied that the liaisons represented at the consultancy were
there to hear the presentations, understand discussion and provide
technical background. As recommended by IOM, there will be multiple
stakeholders, including the other HHS agencies, in the NVAC review. The
ISO is collaborating with NVPO to obtain input from the other federal
agencies as the preliminary research agenda is being drafted, which
would include colleagues in the FDA and NIH, as well as other federal
agencies.]{.mark}

[]{.mark}

**[[UPDATE: HERPES ZOSTER VACCINE SAFETY]{.underline}]{.mark}**

**[Dr. John Treanor, ACIP WG Chair]{.mark}**

**[Dr. Sandra Chaves, CDC/NCIRD/DVD]{.mark}**

[]{.mark}

[**Dr. Treanor** noted that as of January 2007 approximately 350,000
doses of zoster vaccine had been administered. It is complicated but
interesting to look at adverse events in a population with many
concurrent medical events.]{.mark}

[**Dr. Chaves** reminded the committee that the vaccine was licensed in
May 2006, and by October, it was recommended for adults age 60 years and
older. Injection-site reaction was the main adverse event reported
during clinical trials, and it was clearly more frequent among those
receiving the vaccine. There were no other clinically important or
statistically significant differences observed regarding systemic or
serious adverse experiences. However, in the adverse event monitoring
substudy, where approximately 6,000 people were closely followed, the
rate of serious adverse events was higher among those receiving the
vaccine compared to those receiving placebo, but no clinical pattern was
identified.]{.mark}

[This safety update was based on data from VAERS, which uses a coding
system to computerize reported events and as a way of standardizing
complaints. A report is classified as serious if a patient reported
having been hospitalized or if the patient died or had any
life-threatening or disabling illness or any other medically important
condition.]{.mark}

[VAERS received 590 reports through June 1^st^, which represents an
overall reporting rate of 73.3 per 100,000 doses distributed. These
rates are based on preliminary data provided by the manufacturer. Among
those, 44 reports were characterized as serious, for a reporting rate of
5.5 per 100,000 doses. Two were deaths.]{.mark}

[Among the 590 reports, over half were women, and for reports classified
as serious, 43 percent, 19 out of 44, occurred among those ages 70 to 79
years. It is important to note that 14 percent of all reports
represented people younger than 60 years. This younger group would
represent off-label use or administrative error; many were children
under five, and 50 percent were adults aged 21 to 59. In 90 percent of
the reports, Zostavax was administered alone. The others referred to
concomitant administration of other vaccines that were part of the
childhood immunization program.]{.mark}

[The most common adverse events were injection-site reaction, rash and
zoster. The majority were female and the median age was 65 to 68 years.
The interval between vaccination and event onset was a median of one day
for injection-site reaction, three days for rash, and five days for
zoster. The interval ranged from less than one day to eight to nine
months or up to a year for rash. None of the zoster cases tested so far
has been confirmed to be due to Oka strain, but very few have actually
been tested.]{.mark}

[There were reports of allergic reactions and anaphylaxis occurring soon
after vaccination. Although hospitalization was required, which
automatically classified these reports as serious, they offered very
good outcomes.]{.mark}

[One pregnant woman was inadvertently vaccinated with Zostavax; the
patient actually requested to be vaccinated and then, ten days later,
was found to be pregnant. She is being followed by the pregnancy
registry, but there is no further information on pregnancy
outcome.]{.mark}

[There were three cases of encephalitis. One started with disorientation
within the first 24 hours of vaccination. The MRI did not show any
abnormalities, and CSF was negative for herpes simplex, but no test was
done for VZV. The other two encephalitis cases had very limited data
available.]{.mark}

[Eight events were coded as secondary transmission, five of which were
reports of people developing zoster after being exposed to a spouse who
had been vaccinated with Zostavax. Of the other three, one was a child
who was exposed to his grandparents and developed chickenpox a few days
later. A man was exposed to his wife who had been vaccinated with
Zostavax, and ten days later he developed chickenpox, but it is unlikely
that his chickenpox was a result of this exposure. There was also a
physician who was exposed to a patient who had zoster after being
vaccinated; two weeks later, she found two vesicles that she assumed
could be chickenpox and started antiviral treatment, even though she had
a history of chickenpox during childhood.]{.mark}

[Some of the events were coded as varicella and varicella post
vaccination. Eleven were varicella-like rash occurring after vaccination
with Zostavax, with one case hospitalized due to the extent of the rash,
but no lab data are available for any of these cases. Four reports
classified as varicella post vaccination were actually zoster. Among the
zoster cases, there was a 63-old-woman hospitalized with acute retinal
necrosis and zoster in her right eye, but no further lab information was
available.]{.mark}

[Most of the events coded as medical error or wrong drug administered
were presented as human error or unintentional use of Zostavax instead
of other vaccines, such as Varivax and ProQuad. There were two reports
of immunosuppressed individuals who were inadvertently vaccinated, and
two reports of local injection-site reactions in persons under age 60,
which could represent off-label use.]{.mark}

[Two deaths were reported as temporally associated with the receipt of
the zoster vaccine. Both persons were 80 or older, but clinical-lab
information was not available. For one of the cases, the cause of death
was sepsis and pneumonia, occurring six months after vaccination. The
other had a heart attack a week after vaccination.]{.mark}

[To summarize, Zostavax seems to have a very good safety profile, very
much as expected during clinical trials pre-licensure. The most frequent
reported event is injection-site reaction, although herpes and rash were
very common. There is no way to establish any association with the
vaccine virus without support of laboratory information. It is also
possible that all the zoster captured in the system was a reflection of
vaccine failure since vaccine efficacy was around 60 percent. Many of
the reports describe events related in time, but that is likely caused
by other factors, especially in this age group, where co-morbidity is
common.]{.mark}

[Surveillance is extremely challenging for this vaccine. VAERS is a good
system for providing signals, but a better understanding of
administration errors and off-label use of the vaccine will come from
specific studies. VAERS data are passive surveillance, subject to
underreporting, lack of clinical and laboratory information that would
establish causality, and lack of denominator data. Post-licensure safety
studies are expected to be undertaken, which would add to the safety
profile of the vaccine. CDC, through the Vaccine Safety Datalink and
Kaiser Permanente and Group Health Cooperative, will look at adverse
events among adults 50 years and older. This cutoff age may provide a
better assessment of off-label use of the vaccine. Also, Merck has
agreed to conduct a post-licensure, randomized, placebo-controlled
clinical trial in approximately 12,000 subjects, where half will be
receiving the vaccine and the other half placebo. They will also assess
the use of high-potency doses of Zostavax and the use of lower doses for
people taking corticosteroids.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[Dr. Allos noted that 34 of the administration errors involved children
who were supposed to be receiving Varivax. She wondered if those were
all in just a few sites or if they were randomly distributed, whether
packages looked similar, and whether anything could be done to make them
look more distinctive. Dr. Chaves responded that packaging and labeling
did not seem to be the major issue in the reports. It was really just
unintentional, human mistakes. She did not have any information about
how many sites were involved.]{.mark}

[Dr. Pickering commented that when meningococcal conjugate vaccine first
came out, it was inadvertently given subcutaneously instead of
intramuscularly as was recommended. However, a study of about 100 people
who had blood drawn showed the titers were low but still acceptable, and
they did not need to be immunized again. He wondered what the
recommendation would be for children who get this vaccine, at 14 times
the dose of Varivax, with regard to a second varicella immunization. Dr.
Chaves replied that there was no official recommendation. A two-dose
recommendation was in place for varicella, and one would need to assess
if a higher dose was as efficacious as a two-dose vaccination. Dr. Kuter
from Merck added that they had actually looked at material as high as
50,000 platform units in healthy children and safety was comparable to
their typical dose in the five to 10,000 dose range PFU. However, there
was a plateauing of the response, i.e., the seroconversion rates and
GMTs were comparable whether children were given 5,000 or 50,000 PFU.
Off label, she still recommended that a second dose be given.]{.mark}

**[[COMBINATION VACCINES]{.underline}]{.mark}**

**[Patricia Stinchfield, RN, MS, CPNP, ACIP WG Chair]{.mark}**

[]{.mark}

[**Ms. Stinchfield** explained that the combination vaccine working
group (WG) was reinstated to develop a revised statement on the use of
combination vaccines for review and approval of the ACIP. The last
statement was written in 1999. The long-term goal is to review issues
surrounding the availability and use of combination vaccines. However,
an important and immediate short-term goal was to review an upcoming
vaccine known as Pentacel®, a DTaP-IPV-Hib combination vaccine, in
anticipation of discussion at a future ACIP meeting, pending the FDA
approval.]{.mark}

[Sanofi pasteur submitted the BLA for a four-dose primary series in
children for the two-month, four-month, six-month, and 15- to 18-month
part of the schedule. The FDA requested additional information from
sanofi, which resulted in an extension of the review clock for this BLA.
Pentacel® was approved in Canada in 1996 and in all the jurisdictions by
\'97, \'98. Canada has had an excellent experience with this vaccine,
and any future detailed presentation will include the Canadian
experience.]{.mark}

[Beginning in April, the WG met weekly by conference call. The WG
conducted an overview based on the VRBPAC presentation and looked at the
immunogenicity of the vaccine\'s components. The Canadians presented
their experience with Pentacel®, which is now used exclusively
there.]{.mark}

[The WG talked with the Committee on Infectious Disease about
harmonization and the future recommendations in agreement with what is
already published in the Red Book. There was also discussion about
implementation for special risk populations, such as American-Indian and
Alaskan-native children, and some of the nuances that will have to be
considered for Pentacel® in the childhood immunization schedule.]{.mark}

[Future topics for the WG, pending FDA licensure of the vaccine, will be
a detailed presentation at the October ACIP meeting on Pentacel-related
topics. Work will continue on the draft of the *MMWR* notice to readers,
to be presented for discussion most likely at the February 2008 meeting.
Then, pending FDA licensure and ACIP recommendation, there would be an
ACIP vote on inclusion of Pentacel in the VFC program.]{.mark}

[Other future topics would be to review and prepare communications
regarding combination vaccines new to the market. For example, GSK
recently indicated that the FDA has accepted the BLA for their DTaP-IPV,
which is a pediatric booster vaccine for immunizations against
diphtheria, tetanus, pertussis, and polio at the four- to six-age
group.]{.mark}

[The WG will continue work on updating the *MMWR* statement on
combination vaccines that was written in 1999. Issues will be reviewed
surrounding the availability and use of combination vaccines in the
current U.S. market, after which the statement will be revised and there
will be a discussion about whether to incorporate the combination
vaccine\'s topic into the general recommendations document. Ms.
Stinchfield invited members to offer other agenda items.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Decker explained that Pentacel® was delayed because the
manufacturer moved its global pertussis laboratory testing facilities
into the United States. In association with that, FDA CBER wanted to
review all the comparability data with the existing files for all of the
pertussis products, so licensure of Pentacel® has been held up until
they finish reviewing the lab validation data.]{.mark}

**[[UPDATE: MENINGOCOCCAL CONJUGATE VACCINE
(MCV4)]{.underline}]{.mark}**

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

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

**[Dr. Ismael Ortega-Sanchez, CDC/NCIRD/DVH]{.mark}**

**[Dr. Phil Hosbach, sanofi pasteur]{.mark}**

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

**[Dr. John Iskander, CDC/ISO]{.mark}**

[]{.mark}

[**Dr. Baker** explained that the ACIP MCV4 recommendations were first
published in May of 2005, recommending vaccination of the following
groups: persons aged 11 to 12 years, adolescents at high-school entry,
and other persons at increased risk of invasive meningococcal disease,
including college freshmen living in dormitories. This three-cohort list
was based on supply and risk considerations. The peak of disease in
adolescents begins around entry to high school, and there are strong
data on college freshmen living in dormitories, but there was a desire
to start immunizing the 11-to-12 cohort as well. This was the first
vaccine to go forward, quickly followed by Tdap and HPV, the major
tenets of the adolescent platform.]{.mark}

[Then there was a supply-demand issue, so an *MMWR* notice in May 2006
deferred the 11- to 12-year-olds because they were at baseline level of
risk. When supply became abundant again, an October *MMWR* notice told
people to resume the 11- to 12-year-old recommendation, but this was not
well implemented. There is currently an excess supply.]{.mark}

[]{.mark}

**[Epidemiology]{.mark}**

[**Dr. Cohn** provided an overview of the current epidemiology of
meningococcal disease in the United States, including recent trends and
the burden in adolescents and young adults. The national passive
surveillance system, known as NETSS, receives case reports from all 50
states and provides the numbers seen in the *MMWR*. ABC is an active
laboratory and population-based surveillance system composed of ten
sites in the U.S. Their data are important for serogroup and additional
clinical information on cases.]{.mark}

[Data on the incidence of meningococcal disease in the United States
from 1970 to 2005 show a cyclical waxing and waning pattern with peaks
every eight to ten years. The case-fatality rate decreased in the 1970s
but has remained between 5 and 10 percent since the 1980s. 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. Since 2002 Serogroup B has
caused the highest disease incidence, but there is currently no vaccine
available in the U.S. that protects against that disease.]{.mark}

[Rates of meningococcal disease are highest in infants under one year
and remain high in one- to four-year-olds, age groups for which there is
currently no effective vaccine. Seventy-five percent of
vaccine-preventable cases are in persons 11 years and older.]{.mark}

[The 2005 MCV4 recommendations were made to impact the second peak in
adolescents, who have the greatest burden of disease among the age
groups for which MCV4 is currently licensed. Disease incidence increases
through adolescence, peaking in 18-year-olds. Although the duration of
protection from MCV4 was unknown, it was anticipated that when given to
11- and 12-year-olds, the vaccine would remain effective through late
adolescence. The vaccine was also recommended at high-school entry to
correspond to the rising risk.]{.mark}

[Most cases of meningococcal disease occur in previously healthy
children and young adults. Case-fatality rates among adolescents and
young adults are higher than among children less than ten years old and
above the overall case-fatality rate of 12 percent. Achieving high
coverage with MCV4 could prevent up to 75 percent of cases in 11-19 year
olds. Among children four years old and under, around 50 percent of
cases would be vaccine preventable if a quadrivalent or CY conjugate
vaccine were available. The majority of cases in infants are caused by
Serogroup B.]{.mark}

[In conclusion, meningococcal disease incidence is currently at the
nadir of its normal cyclical disease pattern. Despite implementation of
the MCV4 recommendations in 2005, the CDC does not believe the vaccine
has impacted current disease trends. Meningococcal disease continues to
be a significant cause of morbidity and mortality among adolescents in
the United States. Serogroup B vaccines and safe, effective vaccines for
infants will be needed to achieve meningococcal disease control in the
United States. Vaccinating all persons aged 11 to 18 years with MCV4
would have a substantial impact on disease in this age group. CDC is
conducting vaccine effectiveness and carriage studies and will continue
to use active surveillance to monitor the impact of MCV4 recommendations
and the duration of protection.]{.mark}

[]{.mark}

**[The Economics of Adolescent Meningococcal Vaccination in the U.S.:
Direct and Indirect Protection]{.mark}**

[**Dr. Ortega-Sanchez** talked about the economics of expanding the
adolescent meningococcal vaccination in the U.S. using the
four-serogroup conjugated vaccine. The objective of the study was to see
whether vaccinating most adolescents could significantly and immediately
generate herd-immunity benefits.]{.mark} Therefore, Dr. Ortega-Sanchez's
analysis was focused not only on the direct impact on adolescent
vaccines, but also on the potential herd immunity impact in the rest of
the U.S. population (the indirect impact)

[A Monte Carlo simulation analysis model was constructed, using a one
million 11- to 17-year-old sample representative of a 10 million
population cohort. The vaccination strategy was a one-time mass
vaccination of children ages 11 to 17 years followed by routine
vaccination of each new 11-year-old cohort. The timeframe (or time of
the interventions) is ten years, but the health benefits and costs are
measured over the age-specific life expectancy. The discount rate used
for health costs outcomes was three percent.]{.mark}

[As an illustration of the model the population was stratified into
three age groups: less than 11 years, 11 to 17 years, and 18 years and
older. Direct protection can be achieved for adolescents with
vaccination. Vaccination also offers indirect protection and a safety
net for other age groups who are not vaccinated or for those whom the
vaccine fails to protect. In a ten-year period, approximately 16 of the
cohorts will be vaccinated: seven cohorts in the mass campaign and nine
cohorts of 11-year-olds routinely vaccinated in the subsequent nine
years.]{.mark}

[Epidemiology data included age, year, and serogroup-specific rates, and
the average age- and serogroup-specific case-fatality ratios. The
proportion of survivors with sequelae was also estimated using data from
the literature. Initial vaccine efficacy data were taken from the U.K.
experience with the conjugate Serogroup C vaccination program, which is
in line with the studies of the four-serogroups meningococcal conjugate
vaccine. The study assumed that duration of vaccine efficacy was ten
years, and that vaccine coverage in adolescents was 70 percent, also in
line with the U.K. experience.]{.mark}

[Age-specific incidence data were used for estimating the number of
cases in the population and deaths were calculated using the age- and
sequelae-specific case-fatality ratios. Cases with long-term sequelae
were then calculated using the proportion of meningococcal survivors
with specific sequelae.]{.mark}

[Two studies in the U.K. reported age-specific reductions in cases among
the unvaccinated from vaccination campaigns with the conjugate Serogroup
C vaccine with an average of 57 to 67 percent reductions (Ramsey et al.
and Balmer et al.). These age-specific rates were used to calculate the
number of cases indirectly prevented in the U.S. study.]{.mark}

[Previously published estimates of direct costs were updated to 2006 by
using the gross domestic product (GDP) deflator. It was also assumed
that each active meningococcal case would be hospitalized. Indirect
costs associated with meningococcal disease were used to estimate the
cost of illness per case in each age group. Costs were broken down into
those associated with the acute infectious phase of the disease and
those from long-term complications of permanent sequelae or premature
death.]{.mark}

[A base-case cost of \$83 (range \$50 to \$110) per vaccinee with a
single dose was assumed. Vaccination program costs comprised vaccine,
vaccine administration, and 10 percent vaccine wastage. Costs of adverse
events were included, but time lost by vaccinees or vaccines' caregivers
to get the vaccine was not included.]{.mark}

[Without the vaccination program, an average of 1600 meningococcal cases
attributable to the C, Y, W135 serogroups would have been expected. The
reduction in cases after mass vaccination in 11- to 17-year-olds in Year
1 and the routine vaccination of 11-year-olds in the following years is
represented by two extreme scenarios. The first scenario is the
direct-protection-only scenario, with an average of 156 cases per year,
representing approximately a]{.mark} 9 [percent reduction. The second
scenario is the direct protection plus the full herd-immunity
protection, using the proportions observed in the U.K. with the
meningococcal Serogroup C vaccine. This would avert approximately 835
cases per year in adolescents, which represents a 48 percent reduction.
As seen by these estimates, almost four-fifths of all prevented cases
are attributable to the herd immunity.]{.mark}

[Over a ten -year period, the mass and routine vaccination program will
prevent approximately 8,251 cases, representing approximately 1700
complications and 700 deaths prevented. These reductions will result in
approximately 30,000 life-years saved (15,000 when discounted) or 69,000
QALYs saved (27,000 when discounted).]{.mark}

[A ten-year cost projection to the whole U.S. population found that
meningococcal disease due to the vaccine-containing serogroups will cost
approximately \$1 billion in direct costs and \$1.7 billion in indirect
costs, both after discounting. Before including vaccination program
costs, mass vaccination followed by routine immunization in subsequent
years will save approximately \$1.4 billion over ten years. At \$83 per
vaccinee, the mass and routine vaccination program will cost
approximately \$3.2 billion over ten years, which translates to about
\$223,000 per case averted or \$2.6 million per death prevented. In
assessing the cost-effectiveness of a mass vaccination campaign followed
by the routine vaccination program, the cost to society will be
approximately \$127,000 per life-year saved and \$88,000 per QALY
saved.]{.mark}

[A previous study reported that it was more cost-effective to continue
vaccinating adolescents than toddlers and infants. The Shepard study
published in *Pediatrics* in 2005 did not include herd-immunity impact,
and the vaccine efficacy was assumed to last 20 years. When this study
was updated, with an assumption of a ten-year duration of vaccine
efficacy, the routine vaccination program was less cost-effective than
mass vaccination plus routine vaccination for adolescents. If the most
recent data on the reduction in attack rates, those reported in Ramsay's
study for the U.K., are used, the societal cost drops to \$116,000 per
life-year saved or \$81,000 per QALY saved.]{.mark}

[Regarding indirect protection, mass vaccination followed by routine
program had a net societal cost of \$414,000 per life-year saved,
assuming achievement of only 20 percent herd immunity as reported for
the U.K. If the U.S. can reach the same reductions in attack rates as
the U.K., the cost per life-year saved here will be \$127,000.]{.mark}

[Two recent studies of vaccination in adolescents have also considered
herd immunity, one on pertussis and the other on human papillomavirus.
These studies have shown a lower cost to society per life-year or QALY
saved, which means that they are more cost-effective than mass and
routine immunization with meningococcal conjugate vaccine in
adolescents.]{.mark}

[Two other studies reported cost per life-year saved with a vaccine, but
neither included herd-immunity assumptions. The first looked at the
cost-effectiveness of vaccinating first-year college students in dorms
with the meningococcal polysaccharide vaccine and found that mass
vaccination followed by routine vaccination would be approximately two
times more cost-effective than vaccinating college students living in
dormitories with meningococcal polysaccharide vaccine. The other study
estimated that if the pneumococcal conjugate vaccine were used only to
prevent meningitis in infants, the cost per life-year saved would be
more than \$300,000 (in 2006 U.S. dollars); namely, it would be much
less cost-effective than the mass vaccination program followed by the
routine vaccination.]{.mark}

[The current study has some strengths and limitations. One strength is
the use of complex modeling, which includes direct and indirect effects
of vaccination. It also explicitly used surveillance data for specific
ages and serogroups containing the vaccine. A limitation is that data on
vaccine efficacy and herd immunity are from the U.K. and are not
specific to the U.S. vaccine. In addition, quality of life during the
acute disease was not assessed, and the QALY scores used to assess the
long-term complications are not meningococcal disease-specific.]{.mark}

[In conclusion, the one-time mass vaccination of healthy adolescents
followed by a routine program of 11- to 12-year-olds could have
substantial impact on the burden of disease. Up to 48 percent reduction
of cases could be expected, and 80 percent of these reductions could be
due to herd-immunity impact. However, it would have a net societal cost.
For the same duration of vaccine efficacy, the one-time mass vaccination
followed by routine vaccination could be half as expensive per life-year
saved and QALY saved as routine vaccination of 11- to 12-year-olds
only.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Neuzil asked whether it was reasonable to assume that the U.S.
herd-immunity effects would be the same as the U.K., based on a
mass-vaccination campaign of adolescents followed by routine
vaccination. Dr. Messonnier replied that the U.K. vaccinated everybody
under age 20. It is not clear that the U.S. would see the same impact,
even for 11- to 17-year olds. However, that is probably where much of
the transmission is coming from, which is why an optimistic scenario was
presented.]{.mark}

[Dr. Morse was curious why 11 to 17 was used rather than 11 to 18, and
whether that would make a difference in the cost estimates. Dr.
Ortega-Sanchez responded that 11 to 17 was used for simplicity because
there were approximately one million 11- to 17-year-olds in the 10
million population sample. This does not preclude the possibility that
there will be 16 cohorts vaccinated in a ten-year period, which will
also create herd-immunity impact.]{.mark}

[Dr. Treanor noted that the calculation of cost per QALY saved was first
based on a policy that does not induce herd immunity (routine
vaccination) and then based on mass vaccination, which does induce herd
immunity. He asked whether one would save money by doing a
mass-vaccination campaign. Dr. Ortega-Sanchez answered that when this
study was compared with the Shepard study, assuming ten years duration
of vaccine efficacy and costs in 2006 dollars, the cost per life-year
saved for the mass and routine vaccination program was less than the
cost per life-year saved for the routine vaccination only. Dr. Treanor
further asked about the cost of mass vaccination plus routine
vaccination per QALY saved in the absence of herd immunity. Dr.
Ortega-Sanchez replied that it was more than \$414,000 per life-year
saved.]{.mark}

[ Dr. Lieu said she had the impression that mass vaccination actually
meant catch-up vaccination for the children who did not fall in those
two age bands for whom it is currently recommended. Even assuming zero
herd immunity and that the cost per life-year saved is \$700,000, she
wondered why that was so much higher than what was seen in the original
Shepard analysis, which assumed zero herd immunity and found something
in the range of \$200,000 per life-year saved. Dr. Messonnier explained
that by vaccinating at age 11, the benefits are reaped for the next ten
years, whereas vaccinating a 17-year-old has fewer benefits because the
rates of disease decrease greatly after age 18. Dr. Ortega-Sanchez added
that because most vaccination costs in the model happened in the first
year and that costs close in time usually have bigger weight than cost
in the long run when discounted, the mass vaccination program costs have
a bigger influence than in a routine programs, which are usually
distributed over time.]{.mark}

[Dr. Schaffner noted that much of the motivation for the initial
recommendations came out of the epidemiology of meningococcal disease on
college campuses and wondered if there were any efforts to track the
occurrence of meningococcal disease in college campuses subsequently.
Dr. Turner, American College Health, replied that there was no
comprehensive effort to collect data, but that the number of press
reports about individual cases has dropped over the last four or five
years. He added that he had been struck by the data showing that
Serogroup B now is more common than C and Y. This started around 1999 or
2000 when vaccination of these cohorts began, which seemed to imply that
immunizing this group had not had much impact. Dr. Abramson asked what
happened to B in England after mass vaccination in C. Dr. Messonnier
replied that when they began vaccinating, 60 percent of their disease
was B and 40 percent was C. There is currently an increase in B disease,
so the dramatic decline in C was not related to B.]{.mark}

[]{.mark}

**[Vaccine Supply and Demand]{.mark}**

[**Dr. Hosbach** of sanofi pasteur, said that after the recommendation
was made in May 2005, there was a very enthusiastic response in uptake
of Menactra, as shown by claims filed by physicians in the private
sector. Although the recommendations were targeted for three cohorts,
there was a large response in all ages from 11 to 18, with some peaks at
14 and 18. This put pressure on the supply, so the CDC, ACIP and medical
societies decided to temporarily defer 11- to 12-year-olds, after which
the claims shifted to the older age categories.]{.mark}

[With demand held down, the manufacturer was able to stock up on vaccine
without exhausting supply. In fact, at the end of 2006, there were
approximately 2 million doses in the warehouse and there will be twice
the amount of vaccine available this season compared to last year. This
information gave stakeholders and the working group the confidence to
restore the recommendation to include the 11- to 12-year-olds in late
2006. From January through April of 2007, more children were immunized
with Menactra in the private sector than at any other time period. So
people are responding to the revised recommendations and getting
immunized. Tdap was just being introduced during that time, and there
was good uptake of the vaccine in 11- to 12-year-olds, but there was
still a gap between Tdap claims and Menactra claims, which could be a
hang-over effect from the deferral of 11- to 12-year-olds.]{.mark}

[In 2006 sanofi pasteur sold and/or distributed 4.3 million doses and
had a surplus of nearly 2 million doses, which was carried into this
year. Projections, based upon the three-cohort demand, are for an uptake
of around 6.3 million doses, which would have meant a surplus of about 3
million doses. Over 9 million doses will be available in 2007, and in
2008 more than 11 million doses will be available.]{.mark}

[Marketing looked at low-, medium-, and high-uptake scenarios if there
was an 11- to 18-year-recommendation and everyone received one dose of
vaccine. They assumed that the 85 percent or 70 percent immunization
rate would not be achieved for adolescents overnight. Actually, tripling
or doubling the current rate in one year would be quite substantial. But
as a cohort gets immunized over time, it shrinks. Starting with
immunizing the 30 million adolescent cohort in 2006, by 2007 there are
only 27 million to immunize if immunization rates are achieved. By 2008,
there would be 21.7 million people to immunize. Even with an additional
demand for a million-plus doses this year, above the 6.3 million
projected, there would still be a surplus for next year. In fact, the
number of doses required for adolescent immunization will probably peak
at around 7 to 7.5 million doses annually in the next year or two.
Supply for January and September is on track and will exceed 6 million
doses. With the surplus, there will be more than 9 million doses
available.]{.mark}

[Beyond 2007, supply is expected to continue to increase each year, but
as immunization rates increase, the total number of eligible adolescents
will decline. The market peak is not expected to exceed more than 7 or
7.5 million doses over the next three years. However, by that time there
could be a recommendation or an indication for two- to ten-year-olds and
this committee can consider what to do with the surplus doses.]{.mark}

[]{.mark}

**[Vaccine Supply in the Public Sector]{.mark}**

[**Dr. Wallace** covered supply and demand in the public sector. After
implementation of the recommendation, CDC provided allocations to the
states and grantees based on their VFC populations. There already was an
18-year-old demand from the previous polysaccharide recommendation. The
real demand for a new vaccine is unpredictable in the public sector.
There was a lag in 317 and state funding, and the gap seen with all
vaccines. Through the 2005 contract, CDC purchased 1.4 million doses of
MCV4 out of a total national sales of 3.1 million doses, or 46 percent.
This was lower than the 53 or 54 percent seen for all the pediatric and
adolescent vaccines, partly due to the 11-to-12 deferral.]{.mark}

[It is difficult to reach public sector adolescents beyond the age of 11
to 12. Grantees loose assess to some at-risk children as they go into
their teenage years and the public sector is not the majority provider
for 18-year-olds, where demand is highest. Due to that drop in doses
used, there was actually a risk of expiration of vaccine already on the
shelf. Even when restrictions on the 11- to 12-year-olds were removed,
there was no increase in the demand for the vaccine off the CDC
contracts. In summary, the number of doses available to the public
sector is increasing but use is not, resulting in a risk of expiration
of vaccine and missed opportunities for protection.]{.mark}

[]{.mark}

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

[**Dr. Iskander** presented a summary of post-licensure safety data for
Menactra, as well as data on Guillain-Barré syndrome, or GBS, following
Menactra, based mostly on VAERS data, Vaccine Safety Datalink uptake
data, and planned and ongoing studies. Dose-distribution data were
obtained from the manufacturer.]{.mark}

[Through November 2006, a little more than 1,000 adverse event reports
have been received for Menactra. Just over 10 percent of those met the
criteria for serious adverse events. During the same time period, 7.5
million doses of vaccine were distributed. There is no routine ongoing
reporting of numbers of doses administered overall or broken out by age
group, but published data on usage of Menactra can be obtained by
looking at proportionate use by age group and focusing on the transition
from the previous polysaccharide vaccine to the conjugate vaccine. The
overall dose-adjusted reporting rates for Menactra are 14 per 100,000
doses and serious adverse events are just over 1 per 100,000 doses
distributed.]{.mark}

[Most of the reports concern the ages between 11 and 12, gender
distribution is relatively equal, and the majority of reports involve
Menactra given as a single vaccine.]{.mark}

[The most frequently reported symptoms involve pain. Other frequently
reported adverse events include headache, fever, myalgia, vomiting, and
diarrhea. As is common with reports to VAERS, there was a very close
temporal proximity to vaccination in the majority of reported adverse
events. There have been 19 reports of unintentional injury related to
vasovagal syncope. Two of the more significant injuries involved loss of
consciousness following syncope. In addition, there were two instances
of individuals who apparently experienced syncope while driving,
although neither was reported to be injured. There have also been
vaccine-administration errors, but data published in the September 2006
*MMWR* showed no effect on immunogenicity.]{.mark}

[Serious adverse events are those that involve hospitalization, deaths,
disability, or life-threatening injury with no causality inferred or
implied. Three-quarters of those reports involved Menactra given as a
single vaccine. Clinical reviewers at the FDA and CDC categorized them
according to the primary type of event and/or organ system. Most were
neurological in nature, with smaller numbers in a variety of other organ
systems.]{.mark}

[There have been two reports of death following receipt of Menactra. An
18-year-old male died four days after Menactra with cause of death
listed as presumed cardiac arrhythmia. An 11-year-old developed a
headache, vomiting, and abdominal pain nine days after receiving
Menactra and subsequently became encephalopathic. His autopsy revealed
acute hemorrhagic leukoencephalitis, a rare form of acute demyelinating
encephalomyelitis.]{.mark}

[As of 30 April 2007, a total of 19 confirmed Guillain-Barré syndrome
cases within six weeks of Menactra administration had been reported to
VAERS. All but two were among 11- to 19-year-olds with onset 2 to 33
days following vaccination. Six had received concomitant vaccines.
Reports peaked during the summer months of the past two years. All
recovered or are recovering at this time.]{.mark}

[Comparing observed confirmed cases from VAERS within six weeks of
vaccination stratified by age to the background rates obtained from the
Vaccine Safety Datalink and controlling for the seasonality within the
VSD, there appears to be a slightly increased risk among 15- to
19-year-olds. Data analyzed to date indicate that, among more than
140,000 doses administered, zero cases of GBS have been observed within
six weeks of vaccination. The number of expected cases, based on the
background rate observed within the VSD for such a population, would
range between zero and one. Within the VSD, 94 percent of Menactra
recipients are within that 11- to 19-year-old age group, which also
comprises the majority of the GBS reports.]{.mark}

[Harvard Pilgrim Healthcare is undertaking a manufacturer-sponsored
controlled study of GBS following Menactra. They propose to include a
population of approximately 10 million 11- to 18-year-olds, which would
have sufficient power to detect an elevated risk ratio; the Vaccine
Safety Datalink is not large enough to undertake such a study. The
Clinical Immunization Safety Assessment network also continues to
conduct detailed case reviews and focused laboratory evaluation with an
eye toward studies of hosts, such as genetic risk factors.]{.mark}

[For 11- to 19-year-olds overall, there is no statistically significant
evidence of an increased risk of GBS after Menactra vaccination, but
there does appear to be an increased risk within the 15- to 19-year-old
age category. However, this has to be put in the context of the inherent
limitations of VAERS and the uncertainty regarding the background rate
within the VSD. The timing of neurologic symptoms, which has been
consistently within one to five weeks following vaccination among
reported cases, remains of concern.]{.mark}

[In summary, both the overall and serious adverse event reporting rates
are within the average ranges for the VAERS system as a whole. Most
reported events are non-serious and represent local and systemic
reactions, consistent with the pre-licensure safety monitoring.
Potentially preventable events, specifically post-vaccination syncope
and vaccine administration errors, have been detected for Menactra, as
they have been for other newly licensed adolescent vaccines. The small
increased risk for GBS following Menactra in the 15- to 19-year-old age
group persists across several analyses, but these findings do not
represent a definitive study. Among the other serious adverse events
reported following Menactra, both neurological and non-neurological
diagnoses have been reported in relatively small numbers. Because of the
inherent limitations of VAERS, the causal relationship of any individual
event of vaccination is uncertain.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[Dr. Lett asked whether sanofi pasteur had plans for more manufacturing
capacity, since there would be an increased number of doses available in
2008 due to accumulated inventory. Mr. Hosbach replied that the company
was continuing to expand and increase efficiency in the existing
facility, while the new facility would be brought online over
time.]{.mark}

[Dr. Morse noted that there appeared to be sufficient supply to cover
the year, but that the peak occurs in July and August, just before
college begins. He asked if there would be a surge then and whether
there was enough in the pipeline to meet that increased demand. Mr.
Hosbach replied that the company had been carrying somewhere between 1
and 2 million doses in inventory, which could comfortably handle any
summertime surge.]{.mark}

[Dr. Allos reminded everyone that the most common trigger of
Guillain-Barré is Campylobacter infection and that those infections are
frequently asymptomatic and almost always undiagnosed. The surge in
demand for the vaccine occurs at the same time that there is a natural
peaking in the incidence of Campylobacter infection. Of the 19 reported
cases of Guillain-Barré, almost all occurred during that time. When
intensive surveillance was done for Guillain-Barré among children
vaccinated between January and April, there were no cases. The data
suggest that there is no relationship between this vaccine and
Guillain-Barré, but that Campylobacter-associated Guillain-Barré happens
to mirror the timing of when this vaccination is used. Dr. Iskander
responded that there is not a great deal of testing for etiologic
agents, so broader epidemiologic links of these cases to known outbreaks
or known peaks of Campylobacter have not been found. This does not mean
there is no possibility of links. CISA is in fact looking at algorithms
to promote more standard evaluation of GBS, seeking etiologic
agents.]{.mark}

[Dr. Keyserling noted that, given the anticipated approval for the
2-to-10-year indication by the end of this year, there could be a
significant shortfall if there is uptake in that new age group. Dr.
Baker responded that the ACIP does not consider vaccines that are not
approved but the 2-to-10 group is at lower risk than the 11- to
19-year-olds.]{.mark}

[Dr. Lieu pointed out that there can be a lot of confounding in the rate
ratio of 2.5 among 15- to 19-year-olds, but it remains significant after
controlling for seasonality. Dr. Baker noted that a significant
proportion of the cases had received other vaccines at the same time as
Menactra.]{.mark}

[]{.mark}

**[Presentation of New Recommendations]{.mark}**

[**Dr. Cohn** stated that the meningococcal working group proposed
recommending MCV4 for all persons 11 to 18 years old. A change to the
MCV4 recommendation would be published as an *MMWR* notice to readers,
which would have four sections: a review of the May 2005 MCV4
recommendation, the revised MCV4 recommendation, a discussion on the
implementation of the revised recommendation, and a recommendation
addressing persons with a history of GBS.]{.mark}

[The current ACIP recommendation for MCV4 includes routine vaccination
of persons aged 11 to 12 years; adolescents at high-school entry; and
other persons at increased risk of meningococcal disease, including
college freshmen living in dorms. Recommending routine vaccination of
11- to 12-year-olds emphasizes the ACIP-recommended routine healthcare
visit for 11- to 12-year-olds. Vaccination at high-school entry was
intended to target an additional cohort of adolescents, as risk of
disease increases later in adolescence, but implementation of adolescent
recommendations for MCV4 might be affected by short-term supply
limitations.]{.mark}

[The following explains the rationale for changing the MCV4
recommendation at this time: \"*Simplified recommendations for use of
MCV4 could improve coverage, and current and future MCV4 supply is
expected to be sufficient to meet increased vaccine uptake resulting
from simplified recommendations." *]{.mark}

[The revised ACIP MCV4 recommendation would be as follows: *\"ACIP
recommends vaccination with one dose of MCV4 of all 11- to 18-year-olds.
Persons 11 to 12 years old should be routinely vaccinated at the
ACIP-recommended 11- to 12-year-old healthcare visit.\"* Routine
vaccination is also recommended for persons who are at increased risk
for meningococcal disease, including college freshmen living in
dorms.]{.mark}

[The implementation section of the notice to readers will address the
following issues related to improving uptake of MCV4: emphasis on the
11- to 12-year-old recommended healthcare visit; implementation of the
recommendation for college freshmen living in dorms; and timing of
vaccination, including trying to get adolescents vaccinated throughout
the year instead of just during the summer months. The following wording
emphasizes the importance of establishing the 11- to 12-year
implementation visit. \"*ACIP and partner organizations, including the
American Academy of Pediatrics, American Academy of Family Physicians,
American Medical Association, and the Society for Adolescent Medicine
recommend a healthcare visit for 11- and 12-year-olds to receive
appropriate immunizations and other evidence-based preventive services.
*]{.mark}

*[\"A recommendation for MCV4 vaccination among persons 11 to 12 years
old could strengthen the role of this preventive-care visit and have a
positive effect on vaccine coverage of all recommended adolescent
vaccines."]{.mark}*

[To address vaccination of college freshmen, *"College freshmen living
in dormitories are at increased risk of meningococcal disease and should
be vaccinated with MCV4 before college entry, if not previously. Because
of these ability restraints in targeting freshmen in dormitories,
colleges may elect to target their vaccination campaigns to all
matriculating freshmen.\" *]{.mark}

[The following section encourages providers to vaccinate at any
healthcare visit throughout the year*. "Because the incidence of
meningococcal disease increases during adolescence, healthcare providers
should take the opportunity to vaccinate previously unvaccinated 11- to
18-year-olds with MCV4 at the earliest possible healthcare visit. ACIP
encourages healthcare providers to vaccinate with MCV4 throughout the
year to minimize seasonal increases in demand associated with
back-to-school months. Providers may want to consider that VFC
eligibility lapses after 18 years old when making decisions about
vaccination." *]{.mark}

[A draft notice to readers addresses CDC guidance for persons with a
history of GBS. *"Because of the reported association of Guillain-Barré
syndrome after receipt of MCV4, persons with a history of GBS may be at
increased risk and should discuss the risk of meningococcal disease with
their healthcare provider when deciding whether or not to be
vaccinated." *]{.mark}

[This change to the MCV4 recommendation would parallel Tdap and HPV
recommendations in the proposed 2008 adolescent immunization schedule.
The language in the current MCV4-VFC resolution covers qualified
adolescents 11 to 18 years old and would not need to be changed. In
conclusion, the meningococcal ACIP working group anticipates that these
recommendations would simplify provider decisions to vaccinate and
improve adolescent coverage with meningococcal conjugate
vaccine.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Hull referred to information from Dr. Ortega-Sanchez about uptake
over three to five years, which would blunt the herd immunity as well as
the individual protection provided, and wondered what effect that would
have on cost-effectiveness estimates. Dr. Schuchat commented that herd
immunity does not necessarily require a mass-vaccination campaign. There
are many unknowns with meningococcal conjugate quadrivalent vaccine
because nobody has evaluated herd immunity yet. However, there was
tremendous herd immunity with the pneumococcal conjugate vaccine in
infants, without an effective effort at catch-up. The same was true for
the Hib vaccine. So using the healthcare visits to vaccinate anybody in
that age group, one could realistically expect some herd immunity with
this opportunistic vaccination. Dr. Ortega-Sanchez responded that the
analysis was based on using a comparator in the no-vaccination scenario.
Some vaccination is already happening, but there many places where the
uptake has been very slow. He was not sure whether changing the baseline
scenario of no vaccination to some vaccination would change the cost per
life-year saved or reduce cost-effectiveness numbers.]{.mark}

[Dr. Lett asked whether the recommendation referred to a
mass-vaccination campaign or routine catch-up over a period of years.
Dr. Abramson replied that it was catching up. Dr. Cohn added that it was
about opportunistic vaccination as soon as possible.]{.mark}

[Dr. Lieu supported the proposed recommendation because the economic
analysis and the Guillain-Barré syndrome analysis make clear that it
would be better to deliver this vaccination at the 11- to 12-year-old
age range or earlier in adolescence rather than later. On the basis of
consistency and common sense, providers would clearly vaccinate a
17-year-old about to enter college, even though it is less cost
effective.]{.mark}

[Dr. Neuzil asked whether there was any evidence or biological
plausibility to say someone who has had GBS would be more at risk for it
from a different antigen. Dr. Allos did not believe there was any
biological basis, but noted that there has been a statement about
Guillain-Barré in all the new vaccines. Dr. Iskander added that in the
vast majority of all cases, specific etiology is unknown, but once
someone has had it, subsequent risk is increased globally. It is
important to avoid or disentangle coincidental cases. One of the initial
five sentinel cases was someone who had a third post-vaccination
recurrent case with a common antigen. Dr. Abramson reminded everyone
that people with a previous episode of Guillain-Barré were advised not
to get an influenza vaccination.]{.mark}

[Dr. Gilsdorf felt there had to be a balance between the fact that the
magnitude of GBS goes up with use of the vaccine and the fact that the
disease is quite rare. Dr. Abramson added that the incidence of GBS goes
up in the 15-17 age group.]{.mark}

[Dr. Schuchat recalled that at the February meeting there was a decision
analysis that looked at a ten-year framework in terms of estimated
prevention of cases and deaths caused by meningococcal disease, as well
as episodes and possibly deaths from Guillain-Barré syndrome, and the
numbers were very much skewed towards the benefits of
vaccination.]{.mark}

[Dr. Pickering pointed out that death due to mening is clearly worse
than Guillain-Barré, but the long-term effects in adults with CNS
problems from Guillain-Barré are quite significant. He asked whether the
ISO had any plans to utilize CISA units to look at long-term CNS
problems or even the genomics of this disease in the people who develop
it. Dr. Iskander responded that there were several research protocols
moving forward. The idea is to look at rare but instructive issues, such
as recurrent GBS or recurrent post-vaccination GBS. The ISO also
sponsors some animal model studies to get to underlying pathophysiologic
mechanisms. Some of the most compelling cases in the literature suggest
an underlying genetic or host-factor basis. The CISA network has
identified this clinical entity as a priority.]{.mark}

[Dr. Baker noted that if one included the entire 11- to 18-year-old
cohort, the risk of invasive meningococcal disease was 0 .5; in college
freshmen living in dormitories, it was 3 to 4 per 100,000, with a
conservative 10 percent death rate and another 20 percent with long-term
sequelae. She thought the increased risk of Guillain-Barré in MCV4
recipients was a little more than one per million. Dr. Iskander agreed
but pointed out that this was not the analysis from which one would want
to extrapolate attributable risk or etiologic fraction. Depending on
when the analysis is done seasonally, it is between one to three
attributable cases per million doses.]{.mark}

[Dr. Baker asked about the outcomes of reported cases in adolescence.
Dr. Iskander replied that there had been no deaths and one or two
individuals may still be undergoing rehabilitation. The more difficult
question is the one of long-term sequelae and neurologic conditions in
general.]{.mark}

[Dr. Turner, American College Health., recalled that for every million
doses of Menactra administered, it was predicted that about 60 cases
would be prevented among 17- and 18-year-olds, with 1.25 additional
cases of GBS. So the risks must be weighed against the benefits.]{.mark}

[Dr. Treanor felt the recommendation made good sense, but since children
make relatively few visits after the 11- to 12-year-old visit, he
wondered what the practical consequences of giving vaccines as the
opportunity presented itself would be in terms of vaccination rates. Dr.
Middleman from the Society of Adolescent Medicine reported that about 34
percent of adolescents make a preventive-healthcare visit, but 80 and 90
percent can identify a primary healthcare provider and about 70 to 80
percent have some contact with either an ED or a physician for another
reason. So there are multiple missed opportunities. She added that from
a practical perspective, the new recommendation makes it simpler to
protect more adolescents. Dr. Temte from the AAFP noted that data for
Wisconsin show no difference between the number of visits for children
zero to ten and the number for those ages 10 to 20. However most of the
zero-to-ten visits are preventive, whereas the others are episodic
acute-care visits. Ms. Stinchfield added that most clinicians were
already giving the vaccine because they fear the disease so much. Dr.
Baker emphasized the need for more education to expand
opportunities.]{.mark}

[Dr. Abramson asked whether the preference for simultaneous
administration of Tdap and meningococcal vaccine needed to be repeated.
Dr. Messonnier said that could be added to the notice to
readers.]{.mark}

[]{.mark}

[]{.mark}

**[Vote]{.mark}**

[ Dr. Baker moved that the committee approve the recommendations as
reviewed. Dr. Allos seconded the motion.]{.mark}

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

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

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

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

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

[Dr. Lett : no.]{.mark}

[Dr. Lieu : yes.]{.mark}

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

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

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

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

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

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

[]{.mark}

[Dr. Lett stated that it seemed a little premature to change the
recommendation. Providers have been confused and changing so quickly may
be disruptive. She felt it would be better to wait another
season.]{.mark}

**[[PROPOSED APPROACH TO ECONOMIC ANALYSIS OF VACCINES AND IMMUNIZATION
STRATEGIES UNDER CONSIDERATION BY THE ACIP]{.underline}]{.mark}**

**[Dr. Tracy Lieu, ACIP]{.mark}**

**[Dr. Mark Messonnier, CDC, NCIRD/ISD]{.mark}**

**[Dr. Martin Meltzer, CDC/NCIRD/OD]{.mark}**

[]{.mark}

[**Dr. Lieu** explained that ACIP\'s charter recommends that committee
deliberations should include consideration of population-based studies,
such as efficacy, cost-benefit, and risk-benefit analysis. Since October
2004, there have been economic presentations on meningococcal vaccine,
pertussis for adolescents, adults and healthcare workers, Varicella\'s
second dose, Hepatitis A, HPV, rotavirus, zoster, and rabies
post-exposure prophylaxis. These cost-effectiveness studies typically
use decision-analysis or computerized models, and are based on
assumptions about vaccine effectiveness, disease epidemiology, vaccine
cost, and duration of immunity. Those assumptions are not based on
empirical studies, so economic analyses are particularly easy to bias.
They are also hard to understand because there are so many numbers and
each presenter uses a slightly different format to present the data.
Therefore, the ACIP formed a working group to look at standardization of
methods used to offer information to the committee. Recommendations were
drafted based on existing standards set up by the U.S. Preventive Health
Service. The gist of those recommendations is that every economic study
should be carefully reviewed by CDC economists before being presented to
ACIP or its working groups in order to ensure that the best information
available is given to the committee or working groups as decisions are
being made.]{.mark}

[]{.mark}

[**Dr. Messonnier** talked about what needed to be included in a study
and how it should be presented. Around 11 years ago, the *British
Medical Journal,* developed a checklist for editors and reviewers to
judge whether a submitted study was sufficient for publication.
*Vaccine*]{.mark} [followed suit. Many professional economic
organizations require papers to be submitted in advance of their annual
meetings as well. The working group has been working on a set of
standards, which is almost complete. Basically they require submission
of a manuscript comparable to a journal article, with less detail on
introduction and discussion, and more detail on methods and results.
There will be no word limit so as to get the fullest explanation
possible. A set of presentation slides will also be required in advance.
A suggested template is available, though not required.]{.mark}

[The material should be submitted to the working group chair and a CDC
liaison eight weeks before the general meeting in order to find a
reviewer. This includes internal CDC studies as well. Extraordinary
exceptions will be allowed, but not failure to plan.]{.mark}

[There will be an internal anonymous peer review, coordinated by the
NCIRD\'s lead economist. That reviewer can consult with subject-matter
experts at CDC, but the completed review should be back to the working
group chair and the CDC liaison at least four weeks before the general
meeting to allow time for discussion, review, revision and a decision
about whether to present it. The author must provide affiliations and
statements about potential conflicts of interest.]{.mark}

[Details on methods are contained in the text document, but there are a
few main points. First the study question must be clearly and adequately
stated and the perspective must be societal because this is a public
policy decision-making body. Other perspectives\-- payer, healthcare
system, patient \-- are invited but not essential.]{.mark}

[The intervention strategies must be clearly specified and described, as
well as the time frame and analytic horizon, and the type of economic
modeling done, whether it is cost utility, cost-effectiveness, or
cost-benefit analysis.]{.mark}

[Technical equations can be included, but preferably in a technical
appendix. The equations and the economic model should be written out in
sentence form. The health outcomes need to be specified, along with any
underlying epidemiologic models. The inputs used and cost values must be
stated, whether they are assumed or measured, together with any
citations from the literature or justifications for those
assumptions.]{.mark}

[The discount rate used needs to be specified and applied to costs and
outcomes. Discounting has nothing to do with inflation, rather with
observations made of people\'s preference for consumption over time.
Undiscounted-form results can also be presented, but the discounting
needs to be applied to all the costs and outcomes.]{.mark}

[There must be a multivariate sensitivity analysis, since changing one
variable is unlikely to leave all other variables completely unchanged.
Sensitivity analyses need to be presented in a clearly defined section
with all the relevant tables and graphs, identifying the most
influential variables. Independent replication is very important---not
exact numbers but somewhere in the ballpark.]{.mark}

[The results section of the manuscript has to answer the study question.
Results must be clearly identified and in one place. Summary measures
have to be clearly presented and match the perspective. Supplementary
results may be presented, preferably in some sort of technical
appendix.]{.mark}

[Tables and graphs should stand alone. They should add value to the
manuscript and not detract from it. Supplementary tables can be included
in an appendix as well. (Tufte is a good source on the guidelines for
presentation of graphical data.)]{.mark}

[Discussion should be limited to study limitations, the study\'s
relation to other relevant studies, or how the results might change if
some assumptions change. Policy implications are not necessary since it
is the ACIP\'s prerogative to think about the policy implications of the
decisions it is about to make.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[Dr. Decker of sanofi pasteur said he felt the guidelines were
reasonable, but was concerned about meeting ACIP and working group
deadlines. Economic societies do require manuscripts, as mentioned, but
they are less concerned about getting studies published rapidly. Some of
the data may not be available to make a decision about costs and
benefits if there was not enough time to get a manuscript written. Dr.
Pickering clarified that what was needed was a descriptive paper that
will allow CDC economists to say this is a scientifically valid study
and be understood by non-economists]{.mark}

[Dr. Decker than asked what would happen if, for example, something was
about to be licensed and there was an economist who was able to brief
the committee but had not written anything. Dr. Schuchat responded that
the ACIP is a volunteer, deliberative body that is making important
decisions for the country, including inclusion of vaccines in the
Vaccines for Children program, which has a huge economic impact. This
committee is asked to understand, digest, deliberate and vote based on
cost-effectiveness data. She felt it was reasonable to expect members to
receive complete, well-documented data, with adequate time for an
independent economist to review and weigh in on them. The working group
is just requesting a complete, interpretable analysis, with documented
methods and assumptions, and results in a standard format.]{.mark}

[Mr. Beck commented that when he joined ACIP, he was absolutely amazed
at the quality of the economic data presented. It would never have been
permitted in the corporate world. He felt there needed to be a system
and a level playing field, and welcomed the new guidelines.]{.mark}

[Dr. Treanor noted that listening to presentations that he could not
understand was actually counterproductive in terms of making a decision.
Dr. Feinberg agreed that it was in everyone\'s best interest to make
sure the data used to make recommendations were as outstanding,
rigorous, and thoroughly vetted as possible. He wondered whether any
thought had been given to seeking external reviewers and what would
happen if there was a difference of opinion between reviewers. Dr.
Pickering responded that the CDC planned to put together a list of CDC
economists as well as outside reviewers who could be contacted for
special expertise. There also needs to be a time line, since
implementation of the new guidelines will be gradual. Regarding Dr.
Feinberg's second question, Dr. Messonnier responded that criticisms had
to be valid and reasonable before there would be rejection of a
manuscript. A provision will be made for comments from the reviewing
economist to be aired as well.]{.mark}

[Dr. Markson from Merck asked how the committee would handle multiple
models, developed by several groups. Dr. Messonnier replied that it
would be up to the working group to decide whether to hear two or three
different estimations on cost-effectiveness or cost benefits.]{.mark}

[]{.mark}

**[[VACCINE SUPPLY AND IMPLEMENTATION]{.underline}]{.mark}**

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

[]{.mark}

[**Dr. Wallace** first gave the committee a brief update on varicella
zoster virus bulk-based vaccines, which include varicella vaccine
(Varivax); MMRV(ProQuad); and the zoster vaccine (Zostavax). When Merck
temporarily suspended production to work out yield issues, the ad-hoc
supply work group recommended no change in the varicella vaccine
vaccination policy, which meant the two-dose schedule should still be
implemented. Merck was prioritizing production of Varivax and Zostavax
and expected MMRV (ProQuad) to be depleted in the third or fourth
quarter of 2007. After announcing the production issues, Merck
experienced record sales of ProQuad, and supply was exhausted by June
15^th^. Any current orders through the CDC contract may not be filled
until July or August. However, there is no change in the recommendation
for vaccination to protect against varicella disease; Varivax supply is
adequate to meet these needs and Varivax and MMR would be given as
separate doses. Mixing the two together to try and make ProQuad will not
work.]{.mark}

[Dr. Wallace then reviewed implementation of adolescent vaccines,
particularly in the public sector. Overall, the CDC contract accounts
for around 50 percent of the national total for pediatric and adolescent
vaccines.]{.mark}

[Regarding public sector demand, CDC started off with around 46 percent
of the Menactra market in 2005. This dropped to 40% in 2006, but there
was a modest increase in the number of doses purchased. Through the
first half of 2007, no increase has been seen, but decisions made
earlier in the meeting may have some impact. Tdap started slowly (24% of
market in 2005), but the contract happened relatively late in the season
and probably missed some of the pre-school vaccination in the public
sector the first year. The market share increased to 41% in the second
year of implementation, but appears to have dropped off in the first
half of 2007. The CDC contract was two months after the licensure for
HPV in 2006, but caught up pretty quickly and has increased the number
of doses purchased.]{.mark}

[Another way to look at adolescent implementation status is as follows:
CDC purchased approximately two cohorts worth of Tdap vaccine in 2006,
but that appears to be falling off in 2007. For HPV, about one cohort of
a three-dose series has been purchased to date and CDC is a bigger
proportion of that market than for other adolescent vaccines. For
Menactra, grantees purchased doses for less than half of a cohort for
each of the last two and a half years, so there is certainly room for
improvement there.]{.mark}

[With the CDC contracts and new vaccines, there tends to be a lot of
enthusiasm for the vaccine early on, but reaching adolescents is still a
big challenge. The adolescent platform is not the same as the pediatric;
the 11- and 12-year-old visit does not have the same coverage as the
four- to six-year-old visit and may involve different providers. Also,
activity in the adolescent arena tends to be disease specific. Grantees
have gotten some pushback by groups with specific vested interests
instead of looking at the big picture. New access strategies need to be
developed and grantees need guidance from others who have learned what
works.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[ Dr. Stanley Plotkin asked whether any thought had been given to
repairing the school-based immunization system. Dr. Schuchat announced
that there would be a supplement to *Pediatrics* focusing on adolescent
immunization, which will pull together results from a workshop about a
year and half ago. It is an area of major importance to CDC and many of
the liaison groups, and will require a lot of creativity. School-based
immunization has been successful in many areas and allows for quite a
bit of public/private collaboration. She also mentioned the September
workshop on school-aged recommendations for influenza, which will
include thought about the school venue. Dr. Abramson added that NVAC
also had an adolescent work group thinking about this issue.]{.mark}

[]{.mark}

**[[UPDATE: PNEUMOCOCCAL WORKING GROUP]{.underline}]{.mark}**

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

[]{.mark}

[**Dr. Morita** explained that the working group's charge was to review
the need and optimal timing for updated statements on the use of the
conjugate vaccine and the polysaccharide vaccines and to develop a
revised statement on the use of the pneumococcal vaccines for ACIP
review and for approval. The polysaccharide vaccine statement was issued
in 1997 and the conjugate vaccine recommendations were issued in 2000.
The group's agenda included any changes to the current recommendations
based on existing data, for example, direct and indirect population
effects from the conjugate vaccine, non-vaccine serotype replacement, or
trends in antimicrobial resistance. In addition, the group reviewed the
conjugate use and effects in special populations, specifically
Alaskan-native and American-Indian children, and alternative vaccine
schedules with reduced number of vaccine doses.]{.mark}

[A number of presentations were made to the working group. Matt Moore
described trends in invasive pneumococcal disease in the U.S. before and
after the conjugate vaccine. Marie Griffin from Vanderbilt reviewed the
population impact of the conjugate vaccine on pneumonia,
hospitalizations, and otitis media visits. Tom Hennessy and Ros
Singleton from Arctic Investigations Program reviewed an increase in
invasive pneumococcal disease in Alaskan-native children due to
serotypes not in the conjugate vaccine and Kate O\'Brien reviewed the
impact of nine years of conjugate vaccine use on invasive pneumococcal
disease among Navajo children. Wyeth Vaccines reviewed the comparative
immunogenicity of conjugate vaccine using a two-plus-one alternative
dosing schedule. Tammy Pilishvili from CDC also reviewed the
post-licensure effectiveness of conjugate vaccine against invasive
pneumococcal disease in the U.S. Pekka Nuorti reviewed the uptake of
conjugate vaccine among children in the United States, and David
Goldblatt reviewed the experience with reduced conjugate dose schedules
in the U.K. Lastly, Philippe DeWals from Canada reviewed the impact of
the three-dose conjugate vaccine program in the province of
Québec.]{.mark}

[Key issues regarding the pneumococcal polysaccharide vaccine include
contradictory data regarding vaccine effectiveness, and limitations of
the polysaccharide vaccine in elderly persons and high-risk groups. It
will also review the duration of protection, safety, and immunogenicity
of revaccination and optimal timing and frequency of revaccination. The
goal is to look at the overall achievable public health impact.]{.mark}

[Lisa Jackson reviewed contemporary studies of the polysaccharide
vaccine efficacy and effectiveness. Outcomes included invasive disease,
pneumonia, and mortality. Those study designs included clinical trials,
observational studies, and ecological studies. Considerations regarding
revaccination with polysaccharide vaccine include the duration of
protection, safety, immunogenicity, and effectiveness of first
revaccination; safety of multiple revaccinations; and the optimal timing
and frequency of revaccination.]{.mark}

[Before the October meeting, the group hopes to look at possible new
polysaccharide target groups based on available data regarding newly
identified risk groups; the polysaccharide programmatic and
implementation issues; some updated polysaccharide and conjugate
economic studies; and the manufacturer\'s review of potential time lines
for new pneumococcal vaccines in the pipeline.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Abramson asked whether the workgroup would look at the use of a
combination of PCV7 and pneumococcal 23 in the same patient, for example
a sickle-cell patient. Dr. Whitney responded that the group still needed
to go over all those high-risk groups and new data that may have become
available since the last recommendation.]{.mark}

[Dr. Bruce Gellin noted that there needed to be more clarity about the
use of pneumococcal vaccine as part of pandemic preparedness. Advice
from the committee would be welcomed regarding whether people should be
vaccinated now, should there be a stockpile, is there a role for
conjugate vaccine, etc. Dr. Morita replied that this issue was in the
original work plan.]{.mark}

**[[UPDATE FROM THE PREGNANCY AND BREAST-FEEDING WORK
GROUP]{.underline}]{.mark}**

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

**[Dr. Stephanie Schrag and Dr. Tami Skoff, CDC, NCIRD/DBD]{.mark}**

[]{.mark}

[**Dr. Neuzil** introduced the new ACIP working group on vaccines during
pregnancy and breast-feeding. The main motivation behind forming this
working group was the recognition that pregnant women and newborns are
at risk for vaccine-preventable diseases, and yet attention toward
vaccine coverage in these groups and vaccine recommendations in these
groups is not always optimal. Recent discussions around new vaccines
like HPV and Tdap highlighted these issues. For HPV, during the catch-up
period women up to age 26 will be vaccinated; for Tdap there has been
concern about harmonization with other professional societies for
pregnancy-specific recommendations.]{.mark}

[]{.mark}

[**Dr. Schrag** explained that the new working group initially spent
time thinking about terms of reference and identified three main tasks.
The first was to review existing recommendations for use of vaccines
during pregnancy and breast-feeding. The second will be to develop
guiding principles to inform development of ACIP recommendations for
pregnant and breast-feeding women as new vaccines are licensed and
existing recommendations are routinely updated. Finally, the group wants
to help resolve inconsistencies within ACIP recommendations and
facilitate harmonization of ACIP recommendations with those of other
professional organizations.]{.mark}

[In addition to three ACIP voting members, the working group has liaison
representatives from AAFP, ACOG, and AAP, as well as from FDA and the
NIH group in charge of maternal vaccine research. There are also many
subject-matter experts representing current vaccines indicated for
adolescents or adults and relevant subject areas, for example,
immunology and health law.]{.mark}

[The work-group membership was identified in January and the first
in-person meeting was held in February at the last ACIP meeting, where
it focused mainly on terms of reference. Since then, the focus has been
on reviewing existing recommendations by conference call.]{.mark}

[]{.mark}

[**Dr. Skoff** briefly summarized some of the general themes uncovered
thus far. The ACIP stated in an *MMWR* that the risk to a developing
fetus from vaccination of the mother during pregnancy is primarily
theoretical, based on the fact that, to date, no evidence exists to
support a risk from vaccinating pregnant women with inactivated virus,
bacterial vaccines, or toxoids. That *MMWR* also stated that the
benefits of vaccinating pregnant women usually outweigh potential risks,
when the likelihood of disease exposure is high, when infection would
pose a risk to the mother or fetus, and when vaccine is unlikely to
cause harm.]{.mark}

[As a starting point, the working group tried to categorize existing
ACIP recommendations and found variation both in the recommendations
themselves and the language of the recommendations. But it did come up
with four general groupings of vaccines. The first group is recommended
for all pregnant women; to date, the only vaccine that falls in this
category is inactivated influenza vaccine. The second is those vaccines
that follow routine adult immunization recommendations regardless of a
woman\'s pregnancy status. The third and largest group is vaccines
recommended for pregnant women only under special circumstances, such as
when exposure risk is high, and the last group includes vaccines that
are not recommended for pregnant women.]{.mark}

[Many of the ACIP recommendations are challenging to interpret. In fact,
it is not uncommon for similar recommendations to use very different
language. Second, there seems to be an inconsistent message about the
role of limited safety and/or efficacy data for some of these vaccines.
For some products, limited data are used to support vaccination of
pregnant women, whereas for others, lack of sufficient data is a reason
against vaccination. When grouping the vaccines based on their
recommendations, it was found that the majority of the vaccines are
recommended for pregnant women when the benefits of vaccination outweigh
the risks to the individual. This type of language places a large burden
on healthcare providers and pregnant women to make responsible decisions
about vaccination during pregnancy. Finally, the ACIP does address the
issue of breast-feeding and makes an overall general statement
supporting vaccination in breast-feeding women, the notable exception
being smallpox vaccine.]{.mark}

[The second work-group call focused on a review of the FDA process for
making indications for the use of vaccines during pregnancy and
breast-feeding. As part of that process, all vaccines must be classified
under one of five pregnancy categories, which are based on the risk of
reproductive and developmental adverse effects and, for certain
categories, on the basis of such risk weighed against potential benefit.
Of the currently licensed vaccines, all but two fall under Category C,
which includes products that lack human data, but for which animal
studies have shown an adverse effect on the fetus or animal studies have
not been done.]{.mark}

[These pregnancy categories are often confusing because they convey the
false impression that there is a gradation of risk among categories and
the same level of risk within any given category. The FDA is improving
pregnancy labeling and considering either changing or creating
alternatives to the current pregnancy categories.]{.mark}

[The group discussed the fact that vaccine companies write the vaccine
labeling and that it is the responsibility of the FDA to review and
approve the label language. The content is constrained by federal
regulations. No implied claims of product use may be made if there is
inadequate evidence of safety or lack of product effectiveness, which
limits what can be printed on the labeling. In general, the language on
the labeling tends to be much more conservative than the language of the
ACIP recommendations, not only for vaccination during pregnancy, but
also during breast-feeding.]{.mark}

[The most recent conference call focused on the recommendations of AAFP,
ACOG, and AAP, which are generally harmonized with ACIP\'s
recommendations, although interpretation may vary. Translation of the
recommendations by the organizations to a more user-friendly and
easy-to-understand language can be challenging and may actually result
in altered content of the original recommendations. The biggest
difference in recommendations was observed for Tdap, which is
recommended for pregnant women by AAP and is under consideration for a
similar recommendation by ACOG.]{.mark}

[The next step is to start discussions on the development of guiding
principles for recommendations for vaccines during pregnancy and
breast-feeding.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[Dr. Schaffner expressed surprise that Td did not fit into the universal
pregnancy immunization category. It was his impression that before the
ACIP made its recommendation regarding influenza vaccine, the vaccine
was universally recommended. Dr. Neuzil responded that this confusion
was related to inconsistencies in the way recommendations were worded.
Td is recommended for pregnant women if they are unvaccinated, or due
for a booster. Dr. Houn of the FDA added that Category C actually has
two meanings, which is confusing. One is that there is an absence of
animal data as well as an absence of human data, which is probably the
case for Td. The second is that the animal data show adverse effects but
there is absent human data.]{.mark}

[Dr. Baker clarified that the FDA was consistent about Td, so it belongs
in Category C, as does influenza. Both are recommended on the basis of
public health issues. HPV did pass into Category B. To obtain category
B, the vaccine manufacturers must request that category and then provide
the data, and the minimal data are animal data. She felt the FDA rules
were very straightforward and that the disconcerting thing was that
Category B is considered okay and D is bad.]{.mark}

[Dr. Iskander suggested that the work group could also provide clarity
and education on pregnancy registries, why they exist and what lessons
have been learned from them. It might even be possible to frame some
recommendations about preferential reporting to registries rather than
to other passive surveillance systems. Dr. Whitley-Williams noted that
the Department of Defense has a wonderful registry, which showed that
some pregnant women were inadvertently immunized. Some of the data on
congenital rubella syndrome also come from that database.]{.mark}

[Dr. Peter noted that there was a lot of research going on regarding
immunizing pregnant women to protect the newborn, which should give the
working group considerable work in the future. Dr. Neuzil added that the
group was looking at burden of illness both in the pregnant women and in
the newborn.]{.mark}

[Dr. Plotkin emphasized that if the group could come up with general
conclusions, it would be very helpful in trying to convince
manufacturers to develop vaccines that would be used in pregnancy and
would provide some protection in legal matters. He also commented that
assessing the risk of disease in the pregnant woman was inherently
difficult, and favored taking that aspect out. For example, risk is a
very difficult way of evaluating whether to give a vaccine to a woman
who is traveling.]{.mark}

[]{.mark}

[]{.mark}

# [Day Two June 28, 2007]{.mark}

# []{.mark}

# [[INFLUENZA VACCINES]{.underline}]{.mark}

# [Dr. Ban Mishu Allos, WG Chair]{.mark}

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

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

**[Dr. Karen Broder, CDC/ISO]{.mark}**

**[Dr. Gina Mootrey, CDC/NCIRD/ISD]{.mark}**

[]{.mark}

[Dr. Fiore thanked the departing influenza work-group members who are
also members of the ACIP and noted that during their tenure vaccination
was expanded to include children aged 23 to 59 months old and their
household contacts, and a framework and a time line were laid out for
expanding the recommendations to additional ages and groups.]{.mark}

[]{.mark}

## [Influenza Activity in the US during 2006-2007]{.mark}

[**Dr. Fiore** presented data from laboratory surveillance conducted by
the U.S., the World Health Organization and the National Respiratory and
Enteric Virus Surveillance System through June 5th, 2007. Since October
1st, about 173,000 specimens have been tested for flu viruses, of which
13 percent were positive. Among the 22,000 positives, 79 percent were
influenza A and 21 percent were influenza B. About a third of the
influenza A viruses have been subtyped: 64 percent were influenza A-H1
viruses and the rest were H3 viruses. The season peaked in mid to late
February. The intensity and peak time were similar to the previous two
seasons. Deaths attributed to pneumonia and influenza did not exceed the
epidemic threshold during the season, based on information from the
122-city mortality reporting system.]{.mark}

[Laboratory-confirmed influenza-associated pediatric hospitalization is
tracked in several population-based surveillance networks. Rates for
this past season were similar to the rates of the past two seasons, for
children aged 4 and under and for children 5-17 years old, and were
considerably below the rates observed during the 2003-2004 season. As of
June 22nd, CDC had received 67 reports of influenza-associated pediatric
deaths this season, compared to 45 and 46 deaths, respectively, in the
last two seasons, and about 153 in the 2003-2004 season when reporting
began.]{.mark}

[Compared to the previous two seasons, there has been an increase in the
mean age of reported influenza deaths to seven years from four to five
years in 2004 to 2006. There has also been an increase in the proportion
reported to have the invasive MRSA-associated co-infections along with
influenza, from less than 5 percent in the previous two years to 27
percent this past year. CDC and the state health departments are
planning additional investigations and increased surveillance for these
MRSA-influenza co-infections among children.]{.mark}

[Dr. Fiore shifted attention to the time frame for considering expansion
of the recommendations, which may include school-aged children by 2008,
followed by household contacts and caregivers of those school-aged
children and then, by 2012-2013, discussion of implementation of
universal vaccination for all age groups. Expanding the recommendations
to include routine vaccination of school-aged children has been a major
topic in the work-group discussions over the past year. A
CDC/CSTE-sponsored consultation to consider the scientific and
implementation issues raised by the proposed expansion will be held
September 10th and 11th in Atlanta. Approximately 75 consultants have
been invited, including influenza researchers and epidemiologists,
representatives from public health and professional and medical
organizations, community vaccinators, safety experts, and people who
have implemented vaccination programs in school-aged children. The
agenda will include a review of the evidence base supporting expansion
of the recommendations, including the burden of disease in this age
group; vaccine effectiveness and safety; cost analyses; the potential
direct and indirect impact in communities; and experiences and pilot
projects from around the country and in other countries. Key evidence
gaps will be identified. The second day will largely focus on
implementation challenges and the potential solutions, which would
include sustainability, infrastructure and resource needs, the
feasibility of delivering the vaccine in nonmedical and medical
settings, priority communication messages, and how to assess impact over
time. The outcomes of this meeting will be presented at the October 2007
ACIP meeting.]{.mark}

[Dr. Fiore briefly mentioned the strain selections for the upcoming
season, which were made at the VRBPAC meeting and FDA on February 28th.
One strain has been changed out. The A/Solomon Islands/3/2006 strain
will represent the H1N1 antigens. The other two strains are the same as
last season \-- the A/Wisconsin/67/2005 (H3N2) and
B/Malaysia/2506/2004.]{.mark}

[Dr. Fiore introduced a discussion of the FluMist licensure. FluMist was
first licensed in June 2003. The frozen formulation was licensed for use
in healthy persons aged 5 to 49 years. In January 2007, a liquid
formulation was licensed, which allows the product to be shipped and
stored in a refrigerated state. Commercial use was anticipated during
this upcoming flu season. Around the same time, MedImmune submitted a
BLA application to FDA for use of liquid FluMist in children aged 12 to
59 months of age without a history of wheezing and asthma. The analyses
were presented on May 16^th^ to VRBPAC. The primary data source was the
pivotal trial CP-111, published by Belshe, et al, in the *New England*
*Journal of Medicine* in 2007 and also presented here to ACIP, both in
October 2006 and in February 2007, with the later presentation focusing
largely on safety issues. This was a randomized, double-blind active
control with TIV multi-center study, with pre-specified analyses for 6-
to 23-month-olds and 24- to 59-month-olds.]{.mark}

[The FDA concluded that the data indicated that FluMist was safe and
effective in subjects 24 months of age and older. However, among
subjects less than 24 months of age, there were some safety concerns,
including the fact that participants who received FluMist had increased
all-cause hospitalizations, severity of wheezing, and severity of
respiratory events, compared to the TIV-receiving group. FDA also noted
that a history of wheezing was poorly predictive of wheezing post
vaccination among FluMist recipients. Persons with a history of severe
asthma were excluded, but about 20 percent of participants did have a
history of wheezing.]{.mark}

[All of the adverse events were uncommon, mostly among the children 6 to
11 months old. However, the FDA noted that the post hoc analyses
conducted among the 6- to 11-month-olds should be interpreted with
caution, recalling that the pre-specified age-group analyses were for 6-
to 23-month-olds and 24- to 59-month-olds.]{.mark}

[After hearing the evidence, the committee members concluded that
FluMist efficacy was not inferior to TIV. For the safety vote, the
committee was asked whether the data demonstrated that the benefits
would exceed the risk of FluMist in three groups. For children 12 to 59
months of age without a history of wheezing and asthma, the vote was
nine yeses and six no's. For 6- to 23-month-olds, regardless of wheezing
history, the voting was three yeses and 12 no's, and for children 24- to
59-months, regardless of wheezing history, the vote was 15 yeses and
zero no's.]{.mark}

[The FDA decision on licensure is currently on hold pending resolution
of issues identified during manufacturing plant inspections, but this is
not expected to significantly affect availability of FluMist for the
2007-2008 influenza season. MedImmune can continue to manufacture its
products while taking corrective action, however this makes it difficult
to come to a decision on the age-indication change, so the committee
vote as well as the VFC vote will be delayed.]{.mark}

[The influenza working group members agreed that the data indicated that
FluMist efficacy was not inferior to TIV for all the age groups in the
study. In fact, FluMist provided significantly increased efficacy
compared to TIV in the flu year studied. The data also indicated no
safety signal among children 24 months and older with no history of
wheezing. However, there was concern that additional information was
needed, particularly for children 6 to 11 months old, with regard to
wheezing outcomes and all-cause hospitalization rates compared with TIV;
additional information on safety was also needed for children 24 months
of age or older with a history of asthma or wheezing.]{.mark}

[The working group will review the FDA-approved age and medical
indications once they become available. Clinicians and immunization
programs must be able to screen for conditions that are a
contraindication to LAIV use, such as a history of asthma or recurrent
wheezing. The working group will also continue discussions on the
advantages and disadvantages of]{.mark} recommending LAIV over TIV for
healthy young children, based on the interesting but limited data
showing [that LAIV has better efficacy in preventing lab-confirmed
influenza among young children. Finally, safety monitoring will be
critical, including updates from the Vaccine Adverse Events Reporting
System, the Vaccine Safety Datalink, and the other planned postlicensure
safety studies.]{.mark}

[]{.mark}

## [Discussion]{.mark}

[Dr. Neuzil asked whether Dr. Fiore could provide an update on antiviral
resistance from this past year and if there were any plans for a
case-controlled study to get more definitive data on the efficacy of
influenza vaccine in preventing death in children. Dr. Fiore responded
that resistance to the adamantanes continues to be quite high: 80
percent or more and even 100 percent in some parts of the world. So for
this coming year, CDC advises not using the adamantanes for treatment or
chemoprophylaxis of influenza. Resistance to the neuraminidase
inhibitors remains well below 1 percent. For the upcoming season, a
health advisory network letter was sent out to stimulate reporting of
severe illness with MRSA co-infection and not just deaths, with the hope
of capturing larger numbers to expand the study size. CDC is looking for
both influenza virus isolates and MRSA isolates, since it does not have
MRSA isolates from the dozen or so children previously reported. From
the influenza-virus testing, no particular strain appears to be
associated with these co-infections. As cases are accumulated, an
epidemiologic investigation will be carried out using population-based
surveillance systems and then the case-control study will be resumed if
an increase in these co-infections is identified.]{.mark}

[Dr. Morse pointed out that there is a two-year gap in considerations
for the flu vaccine and suggested that this gap could be decreased since
the vaccine supply seems to be increasing steadily. Also, for pandemic
flu preparations, it is probably better to have a larger vaccine supply
available sooner. He wondered whether the timetable could be moved up.
Dr. Allos explained that the working group's goal was universal
protection and that it may not be necessary to vaccinate everybody to
achieve full protection. The reason for the gap is that once all school
children up to the age of 18 have been vaccinated, there needs to be a
period of time when surveillance data can be collected to assess the
decline in flu rates in the elderly populations, based on expanded
vaccination.]{.mark}

[Dr. Poland argued that such a study would be fine in a static
population, but given the number of people who travel each year,
questions about the real impact of the new policy could not be answered.
He also noted that there are many adults not covered by existing
recommendations and the number of deaths among this population was much
greater than those among school-aged children. In addition, millions of
doses of influenza vaccine are thrown away each year, while more
manufacturers are coming into the market, so previous fears about supply
not keeping up with demand were unfounded. Given that there is a vaccine
informed by six decades of efficacy and safety data and annual epidemics
kill tens of thousands of Americans, he recommended moving quickly to
universal vaccination, with an emphasis on specific high-risk target
groups.]{.mark}

[Dr. Baker reminded the audience that there was already a recommendation
to immunize all children 6 to 59 months of age, but less than 20 percent
of that group was actually getting immunized. Physicians and the general
public continue to believe that the vaccine has to be given before
November and young children have to have two doses at least four weeks
apart. However, for the past ten years, 60 percent of the flu seasons
have peaked in February, so vaccination needs to continue through
December and even into January. Everyone was shocked at the Prevnar
efficacy in the un-immunized older population. Young children have
higher titers of flu, and they shed almost twice as many days as do
adults. Thus there is good reason to a better job with pediatric
immunization, followed by surveillance.]{.mark}

[Dr. Baker noted that the National Foundation for Infectious Disease has
a new initiative called the Childhood Influenza Immunization Coalition,
whose goal is to protect children against influenza by communicating
with one strong voice the importance of making influenza immunization a
national health priority. The coalition is led by the Surgeon General
and co-chaired by Dr. Baker. On May 23rd, over 20 of the nation\'s
leading public health, medical, and parent organizations met to discuss
the objectives of the coalition and outline ways to improve immunization
rates. The coalition will educate healthcare professionals and parents
on the importance of vaccinating children throughout the influenza
season and then measure the outcome of their campaign.]{.mark}

[Dr. Poland pointed out that with pertussis the policy is not to
immunize adults to protect children, even though adults are a reservoir
for pertussis. Because all adults cannot be immunized, children are
immunized against pertussis. Similarly, because all children have not
been immunized against influenza, and because of the dynamicity of the
adult population, adults need to be immunized. However, he applauded the
initiation of a new coalition that would push for influenza
immunization.]{.mark}

[Dr. Schuchat asked what kinds of studies were being done on vaccine
effectiveness for direct protection in children. Dr. Fiore responded
that vaccine efficacy studies were going on in several different sites,
including the Marshfield group and the EIP sites, as well as in the new
vaccine surveillance network sites. The aim is to do more rapid efficacy
estimates that would be available shortly after the end of the season.
The past couple of flu seasons have been very mild and the few cases
that were available to study were actually the same circulating strains
in the vaccine. Influenza epidemiology makes it difficult to design
studies that reliably have the power to measure efficacy.]{.mark}

[Dr. Abramson asked whether the timetable would be part of the September
meeting's deliberations. Dr. Allos indicated that it would not. Dr.
Schuchat pointed out that the focus of the September meeting would be on
the first point on the timetable, based on information about
effectiveness, safety, feasibility, and logistics. The rest of the
timetable will depend on what happens with the first point.]{.mark}

[Dr. Treanor observed that because of the extreme variability from
season to season, it may not be possible to gather useful data over a
short time period. A drop in pediatric deaths over a couple of years
could be the result of a vaccination campaign but could also represent
epidemiologic variability.]{.mark}

[Dr. Hosbach of sanofi pasteur asked whether manufacturers would be
invited to the September meeting. Dr. Fiore replied that vaccine supply
was not considered a limiting factor. Dr. Hosbach noted that vaccine
manufacturers were also interested in increasing immunization rates and
that the logistics of immunization was part of their planning for each
flu season. Dr. Lewin of the Biotechnology Industry Organization added
that manufacturers are not just suppliers. They can also provide
guidance on products that are in development and indications, as well as
their experience in distribution and ideas that might help implement
these recommendations smoothly.]{.mark}

[Dr. Tan of the American Medical Association and also representing the
National Influenza Vaccine Summit, advised that physician groups prefer
a simpler recommendation for vaccination and would support moving toward
universal recommendations.]{.mark}

[Dr. Duchin of Seattle, Washington expressed concern about the two-year
observation period after the recommendation to expand to all school-aged
children, particularly in the context of looking at any effect on older
adults. He felt it was a very short time frame and encouraged the
committee to consider ways to facilitate uptake, particularly in the
school setting.]{.mark}

[Ms. Stinchfield requested that there be a phone conference if the FDA
FluMist decision were to come through during the next few weeks. The
issue is time sensitive and there will also have to be public notice.
Dr. Abramson added that the label will probably be for age two and
older, which makes the consideration somewhat easier, but the committee
is getting five new members who must be caught up before there is a
vote.]{.mark}

[]{.mark}

**[Update on FluMist Safety Monitoring]{.mark}**

[**Dr. Broder** reminded the committee that the general approach to
safety monitoring of new vaccines or new indications is to review
prelicensure safety data to identify potential risk from Phase III
prelicensure trials, recognizing that rare adverse events may not be
apparent until wider use. Post marketing data are reviewed and then a
Vaccine Adverse Event Reporting System monitoring plan is developed, as
well as a Vaccine Safety Datalink project plan, where risk is assessed
through near real-time or planned studies. Next the need to create key
case definitions is identified, along with candidate protocols and
special studies that might involve collaboration with other
partners.]{.mark}

[The main study supporting the FluMist age change under consideration
was a multi-center randomized trial. About 50 percent of the subjects
were in the U.S. and the age group was 6 to 59 months. The study group
received FluMist and an intramuscular placebo saline, while the active
control group received TIV plus an intranasal placebo of saline. Each
group enrolled about 4,000 children. Subjects were excluded if they had
a history of severe asthma or medically diagnosed or treated wheezing
within 42 days before enrollment, but they were not excluded for more
mild forms of wheezing. In fact, recurrent wheezing was a criterion for
stratification in the study.]{.mark}

[There were two pre-specified safety outcomes. The primary one was
medically significant wheeze (MSW), and the secondary one was any
wheeze. MSW was the presence of wheezing on physical exam and at least
one of the following: signs of respiratory distress, hypoxemia, or a new
prescription for a daily bronchodilator that was not prescribed on an
as-needed basis.]{.mark}

[The key safety finding was an increased risk for MSW in children age 6
to 23 months after FluMist, compared with TIV. This risk was not
observed in the 24- to 59-month group. Although the breakdown of 6 to 11
months and 12 to 23 months was not an original pre-specified age group,
that risk persists when the data are analyzed that way.]{.mark}

[Compared with TIV recipients, FluMist recipients had more frequent
reports of runny nose, nasal congestion and low-grade fever after
Dose 1. But they had a similar rate of serious adverse events (about 3
percent in both arms), which were rare throughout the study\'s six-month
period. The vast majority of these SAEs were hospitalizations. FluMist
recipients in the age group 6 to 11 months (not a pre-specified age
group) did have an increased risk for all-cause hospitalizations during
that six-month monitoring period for SAEs. In the FluMist group, 6.1
percent of the recipients were hospitalized versus 2.6 in the TIV group.
The rates persisted when looking at respiratory hospitalization versus
all-cause hospitalization, but no supporting biologic mechanism was
apparent.]{.mark}

[Dr. Broder then shared some data from VAERS for the current indication,
which is 5 to 49 years in]{.mark} persons without a history of wheezing
or a[sthma. From licensure through the end of February 2007, VAERS
received 744 reports after FluMist. About 6 percent of the reports
overall were serious, and only 15 reports were received among children
less than five. This was an off-label indication, and none had serious
adverse events. When serious adverse events are linked to age, they are
all less than 10 percent, which is lower than expected for VAERS
reports.]{.mark}

[The most common reported condition overall was respiratory events. In
the pediatric age group, 6 percent of the reports were asthma-wheezing.
Of the 16 reports, 7 had a history of asthma or wheeze, which indicates
off-label use. This raises the question of whether it might be more
likely to occur in a younger group where wheezing is common and
screening might be harder.]{.mark}

[Three questions seem critical. First, when the screening criteria are
established, particularly for exclusion related to wheezing, will the
screening for history of wheezing appropriately identify children who
should or should not receive vaccination? Second, is the safety profile
of FluMist within about six weeks or possibly a little longer after
vaccination comparable to TIV in children less than five years? It will
be important to look at the risk for medically attended wheeze and for
all-cause hospitalization, as well as potential unexpected safety
signals. Finally, if there is some off-label use or if there is a
permission for use in certain wheezing populations, are children with a
history of wheezing in fact at increased risk for wheezing or
hospitalization or other adverse events after FluMist compared with
those who do not have such a history?]{.mark}

[VAERS will be the cornerstone of initial monitoring, particularly if
uptake is low. CDC and FDA scientists will review daily alerts of
serious adverse event reports and other medically important conditions,
including medically important wheezing after FluMist. The second avenue
will be the Vaccine Safety Datalink. The main limitation of VSD is
limited power to assess risk for rare adverse events, particularly if
uptake is low. VSD will examine the clinically important outcomes in
children, especially medically attended wheezing and all-cause
hospitalizations. But the FDA licensure and ACIP recommendation
decisions and the uptake patterns in the VSD will affect specific aims
and methods of the VSD study.]{.mark}

[The Brighton Collaboration is developing standardized case definitions
for wheezing and asthma outcomes, which will be important to communicate
risk information and screening guidance. A primary vehicle will be the
vaccine information statement. Finally, a Phase IV study is under way
among 60,000 FluMist recipients aged 5 to 49 in the Kaiser Permanente
system. This manufacturer-sponsored study has no CDC involvement.
Results are anticipated in 2011.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[Dr. Schaffner asked whether children with a previous history of asthma
and wheezing had more serious cases of influenza and whether
hospitalization was increased. He wondered whether that information was
needed to contrast what is happening after either vaccine. Dr. Abramson
replied that flu was a well-known inducer, however it is not clear that
the virus has to get into the lung to induce asthma. Dr. Iskander
commented that a corollary question was, what is known about the
inactivated influenza vaccine and wheezing? Several VSD studies revealed
that the initial signal of wheezing following inactivated influenza
vaccine was ultimately found to be an artifact of low vaccine coverage
and the fact that children with more severe asthma disease were more
likely to get the vaccine in the first place.]{.mark}

[Dr. Whitley-Williams was concerned about the use of historical
screening for asthma, especially in the 6- to 11-month-old age group.
Wheezing is often associated with upper respiratory tract infections,
which have viral etiology, yet parents may not be aware that the child
has asthma reactive airway disease.]{.mark}

[Since asthma is significantly on the rise in some minority and urban
populations, Dr. Whitley-Williams asked if there was any information
about whether postvaccination wheezing occurred more in any particular
group. Dr. Broder replied that VAERS does not routinely collect that
information. Dr. Walker from MedImmune talked about CP-111, a
multinational study in North America, Europe, and Asia, where about 80
percent of the children were Caucasian. In that study, there were no
appreciable ethnicity differences in terms of asthma rates, although the
Asian population was only about 5 percent. The study did find that rates
were more common in males than females, across the board for both
FluMist and TIV recipients. Dr. Malinoski added that MedImmune had made
three post-marketing commitments with the FDA pending approval, one of
which was a large study in children less than five. It will obviously be
possible to collect ethnicity data within that analysis. MedImmune has
two additional studies that will look at the effectiveness of the label
in excluding children less than 24 months of age and excluding children
and adults with asthma and recurrent wheezing as a surrogate for asthma.
Those studies can be shared with the working group or members of the
safety group at CDC.]{.mark}

[Dr. Malinoski informed the group that the current proposed label was
for children 24 months and above, with warnings and precautions for
anyone with asthma and children less than five with recurrent wheezing
as a surrogate for asthma, so that the label consistently excludes
anyone from 2 to 49 years of age with asthma. Discussions with the FDA
office of compliance are moving forward relative to resolving
manufacturing practices. Both the agency and MedImmune are confident
that 7 million doses will be available this summer.]{.mark}

[]{.mark}

**[2007 National Influenza Vaccine Summit]{.mark}**

[**Dr. Mootrey** provided an overview of this year\'s National Influenza
Vaccine Summit, which took place on April 19 and 20. It has become an
annual meeting co-sponsored by the American Medical Association and the
CDC to discuss influenza vaccine issues with a broad stakeholder base.
There were 190 attendees representing 74 organizations. The
manufacturers estimated that, barring any unforeseen glitches in the
system, up to 132 million doses of vaccine could be expected this year.
Carol Baker described NFID\'s Childhood Influenza Coalition, the
American Lung Association discussed its flu clinic locator and Tony
Fiore presented a summary of the ACIP recommendations. Key issues
discussed were the vaccine composition, the pediatric second dose,
recommended groups, the remaining age groups, the potential time frame
for modifying influenza vaccine recommendations, considerations for
expanding those recommendations, and some future challenges as the
recommendations were expanded. There was quite a bit of discussion of
the fact that ACIP now recommends vaccination for persons, including
school-aged children, who want to reduce the likelihood of becoming ill
with influenza or transmitting influenza to others, should they become
infected.]{.mark}

[There was an emphasis on supply and distribution issues, including the
rationale for post-season shortages, supply challenges, and providers\'
misperceptions regarding the prioritization of vaccine delivery. The CDC
presented some data from the secure data network indicating that private
providers had received proportionately equitable supplies throughout the
2006-2007 season.]{.mark}

[One very active session had to do with legislation. Some legislative
initiatives may present barriers to achieving coverage, for example,
those that prohibit the use of thimerosal in vaccines. Others may
complicate equitable distribution. Several proposals suggest
prioritizing distribution to certain provider groups. There will be an
effort to provide much needed education and information to lawmakers and
community leaders.]{.mark}

[Another session focused on increasing demand for vaccination through a
variety of partnerships. Awards were given for immunization excellence
in three different categories. For extending the season, the
getaflushot.com organization received the award, and they partnered with
an unusual group of food banks. The Virginia Mason Medical Center got
the award for the healthcare worker partnership. Through their mandatory
vaccination program, they have achieved 98 percent vaccination of all of
their staff for the past two years. The seasonal activities award went
to a Maryland elementary school influenza vaccination project; in some
schools, more than 40 percent of the children were vaccinated using two
different models and over 114,000 doses of vaccine were
distributed.]{.mark}

[As far as increasing vaccination coverage, there was a presentation
showing how to measure vaccine use, followed by a discussion about the
length of the season and how to expand it. Dates for the National
Influenza Vaccination Week were presented for the first time. Throughout
the meeting, there was discussion about the need for more timely and
consistent messaging. Other items for discussion included how to better
balance supply and demand; how to track discarded doses and possible
ways to redistribute doses; ideal settings for vaccination; and ways to
expedite and smooth out the vaccine approval, testing, and delivery
process.]{.mark}

[The executive committee of the Summit will continue to work on
improving coverage of healthcare workers and is also encouraging the
formation of an informal legislative task force, whose primary intent
would be educational. Another objective is to develop a simple,
consistent statement on when and who to vaccinate. The current statement
is, *\"The National Influenza Vaccine Summit encourages that every year
influenza vaccine be administered to all people, including school-aged
children, who want to reduce their likelihood of becoming ill of
influenza or transmitting influenza to others as soon as the year\'s
vaccine becomes available. Influenza immunization should continue
throughout the influenza season through the winter months and beyond as
long as vaccine is available."* Suggestions are welcome.]{.mark}

[]{.mark}

## [Discussion]{.mark}

[Dr. Abramson noted that there had been a healthcare summit five years
ago and not much progress had been made. Dr. Schaffner responded that
the National Foundation for Infectious Diseases continues to promote
healthcare worker immunization. However, with rare exceptions where
institutions have been extraordinarily forceful and innovative in
providing influenza vaccine and obliging all healthcare workers to
participate, coverage remains at just about 50 percent. Nurses in
particular are very reluctant to be vaccinated, based on an embedded
myth that one can get flu from the vaccine. In addition, many prominent
physicians remain skeptical about the efficacy of influenza vaccine. So
any suggestions on how to move ahead are welcome.]{.mark}

[Ms. Stinchfield reported that rates had increased by 10 percent in
Minnesota using the declination form. They are also working on real time
IT solutions to track who has come in, who needs follow up and who has
filled out a declination form. The challenge is that the myths are very
strong, very old, and mostly unfounded. The message that all vaccines
are 100 percent effective is not correct, but this in fact underscores
the need to get everybody in so there will be a better immunized
population. A simple message works best: Everybody needs flu vaccine. It
is needed throughout the season. It will help healthcare workers as well
as all the other high-risk populations.]{.mark}

[Dr. Tan of the American Medical Association pointed out that the Summit
executive committee was collaborating with some other organizations to
provide a best-practices package, highlighting three to five facilities
across the country that have successfully increased healthcare worker
immunization rates, starting with the Virginia Mason program. Some of
the techniques were very innovative but also very aggressive. The idea
is to offer a variety of models that work. The Summit Web site \--
www.preventinfluenza.org \-- has a specific healthcare worker site with
all the necessary resources, including a sample declination form that
can be downloaded. It also has guidance from organizations such as the
National Foundation for Infectious Diseases, the HICPAC-ACIP statement
and the joint commission standard.]{.mark}

[Dr. Poland noted that it has been shown that if it is mandated,
healthcare workers get immunized. Out of 5,000 employees, Virginia Mason
had only six leave over the policy. It would be unconscionable to allow
a rubella-naïve nurse to work in a maternity ward because he or she had
misconceptions about rubella vaccine, and this thinking should extend to
influenza vaccine. It has also been shown that informed declination
helps. Finally, trial attorneys now understand that multiple
professional organizations have listed this as the standard of care.
Unfortunately it may take a few well-publicized lawsuits to get everyone
on board in terms of quality and patient safety.]{.mark}

[Dr. Lett wondered if there were any activities to educate legislators
about influenza vaccine, and in particular whether there was going to be
an organized national effort. Dr. Tan replied that the Summit had
already formed an informal task force, which had met twice regarding
legislative issues across the country. An educational fact sheet on the
challenges of influenza vaccine organization will be produced, including
administration, supply, and distribution. Obviously, thimerosal will be
another focus.]{.mark}

[Dr. Iskander noted that if healthcare workers are concerned they may
get the flu from the vaccine, then perhaps it is time to study that
issue in more depth rather just a lot of hand wringing. Dr. Abramson
responded that the question of whether this was a safety issue had been
raised with OSHA and their answer was, \"We did not have proof that
patients did not give the flu to healthcare workers.\"]{.mark}

[Dr. Sumaya said that if the healthcare system only relies on
individuals to implement immunization schedules, coverage would always
remain at 50 to 70 percent. Although it sounds militaristic, it might be
necessary to make immunization more obligatory. Healthcare workers are
familiar with the safety and quality issues, so it may be one place
where there can be stronger urging, such as making immunization coverage
part of hospital accreditation or part of individual performance
evaluations. There would always have to be a mechanism for opting out,
but the issue is something the ACIP could tackle.]{.mark}

[Dr. Turner of American College Health thought there had already been an
effort to consolidate messages and make them consistent. He asked
whether last year's vaccine production goals had been met, whether the
messaging had resulted in an increased uptake and whether there had been
an appraisal or assessment of last year's efforts. Dr. Wallace replied
that manufacturers produced around 120 millions doses and that 102.5
million were distributed. He did not know how many doses were
administered.]{.mark}

[Dr. Decker suggested that NIOSH could take an active role in the
influenza-among-healthcare-workers issue and provide some science to
guide OSHA. Dr. Landry of GSK added that this could be viewed as a
quality-improvement measure for hospitals and that NCQA should be
approached as well.]{.mark}

[Dr. Abramson thanked Dr. Allos for her work on the influenza working
group.]{.mark}

**[[USE OF VACCINES IN PERSONS WITH HIV/AIDS]{.underline}]{.mark}**

**[Dr. Jane Seward, CDC/NCIRD/DVD]{.mark}**

[**Dr. Gina Mootrey, CDC/NCIRD/ISD**]{.mark}

[]{.mark}

**[Children and Adolescents]{.mark}**

[**Dr. Seward** focused on changes made in the immunization schedule for
HIV-exposed and infected children and adolescents. The term 'exposed' is
used because infants cannot be called 'infected' until definitive
testing has been done. New guidelines are being developed for prevention
and treatment of opportunistic infections in this population, as a
collaboration among CDC, NIH, and IDSA. The new guidelines will be
divided into 2 documents, one for children and the other for adults.
Accompanying the guidelines for children will be vaccine schedules for
zero-to-six and 7- to 18-year-olds. Another group is developing the
document for adults which will include the vaccine schedule for adults
(≥ 18 years). Publication of both documents as *MMWR*s is expected
sometime in the fall, but they will be updated on the Web as new data
related to prevention and treatment of opportunistic infections become
available and ACIP recommendations are passed.]{.mark}

[The published 2007 immunization schedule for all children in the three
different age groups was modified with specific HIV language, taken from
published ACIP recommendations. The footnote language was clarified in
discussion with CDC subject-matter experts. The colors of the bars on
the immunization schedule were also changed, based on recommendations
for HIV-status. Draft schedules were shared with CDC, NIH, and the IDSA
working groups. The zero-to-six and 7-to-18 schedules were presented to
the harmonized working group and they suggested that the ACIP vote on
the schedules specifically because of the rotavirus language. There are
no plans to harmonize the schedule with AAP and AAFP because of the
small number of children involved. They suggested just staying with the
ACIP recommendations.]{.mark}

[The rotavirus language is as follows: *\"No safety or efficacy data are
available for the administration of rotavirus vaccine to infants who are
potentially immunocompromised, including infants with HIV.*\" (That
language is right now in the footnote.) *\"Data are insufficient from
the clinical trials to support administration of rotavirus vaccine to
infants with indeterminate HIV status who are born to mothers with
HIV/AIDS. Practitioners should consider the potential risks and benefits
of administering rotavirus vaccine to infants with known or suspected
altered immunocompetence.\"* (That language includes HIV-infected
infants.)]{.mark}

[The existing language already provided the option for physicians to
vaccinate after weighing the risks and benefits, but the \"*however*\"
language supports vaccination of HIV-infected infants.]{.mark}

[There are 6,000 to 7,000 HIV-exposed infants born each year in the
United States. HIV status is not definitively known by six weeks, but
most will be presumptively negative until they have been tested. They
cannot be definitively negative until four months of age according to
current guidelines. Only 100 or 200 will eventually test positive and
those are basically infants of mothers who did not get any prenatal care
and did not receive HIV prophylaxis during pregnancy.]{.mark}

[Rotavirus is a ubiquitous infection in childhood. Virtually every child
in this country and other countries will become infected by five years
of age. So if these children are not vaccinated, they will certainly
come down with wild rotavirus disease. RotaTeq is the only vaccine
licensed in this country currently and that strain is considerably
attenuated with a very low incidence of fever, other constitutional
symptoms, or viral shedding. Available data suggest that rotavirus
disease is not more severe in HIV-infected infants, which propelled the
commencement of trials in HIV-infected children in Africa.]{.mark}

[The same studies that showed no difference in disease severity did show
higher all-cause mortality in HIV-infected children during four weeks of
follow-up after rotavirus illness, but the significance of that is
unknown because it was not directly related to the rotavirus
illness.]{.mark}

[Most of the studies comparing rotavirus disease severity between
HIV-infected and non-infected infants were done in infants, and more
data are needed on disease severity in older, immunosuppressed
HIV-infected children. It may be that in countries without good HIV
treatment, there are differences as children become more
immunocompromised.]{.mark}

[Oral polio vaccine replicates much more robustly in the intestinal
tract with a much higher viral-shedding risk than RotaTeq, and it is
considered to be safe and is immunogenic in HIV-infected children,
according to two published studies.]{.mark}

[No trials with rotavirus vaccine are planned for the U.S. in
HIV-infected infants, mainly because there are not enough infants to do
a study. In developing countries, where the numbers of HIV-infected
children are higher, co-morbidities are also higher, especially
malnutrition, and the rotavirus disease mortality and burden are
significantly higher. Trials with both the GSK and Merck rotavirus
vaccines are under way or planned. It is not known when those data will
become available, but presumably not anytime soon.]{.mark}

[The fact that no safety or efficacy data are available is in the ACIP
statement already. However, the following considerations support
vaccination of HIV-infected infants. One, the HIV diagnosis may not be
established before the age of the first rotavirus vaccine dose. Only 1.5
to 3 percent of HIV-exposed infants in the U.S. will eventually test HIV
positive. Two, natural rotavirus infection does not appear to be more
severe in HIV-infected infants. And three, RotaTeq vaccine is
considerably attenuated.]{.mark}

[When these data were presented to the NIH, CDC, IDSA group, there was
considerable discussion about the safety of giving the vaccine to
HIV-infected infants. Use of RotaTeq vaccine in HIV-exposed or infected
children was discussed when vaccine policy recommendations were made by
the ACIP. It was considered to be the intent of the ACIP to administer
the vaccine to those infants, but the statement did not state that
intent strongly. After the meeting, the group expressed discomfort with
giving the vaccine to HIV-infected infants because of lack of safety and
efficacy data. Another suggestion was to change the title of this
schedule to "HIV-exposed and infected infants".]{.mark}

[The schedule for children age zero to six years follows the same order
as the regular schedule with the following changes to some of the bar
colors. For influenza, HIV status is considered one of the high-risk
groups so this vaccine is recommended annually for HIV-infected children
and the bar color is changed accordingly from purple (high-risk groups)
to yellow (routine recommendation). For MMR and varicella, there is red
language saying: \"Do not administer to severely immunosuppressed
children.\" For hep A and mening polysaccharide vaccine, these children
are not in the high-risk group, but they could be if they had additional
areas of residence or conditions, so the bar is left purple. They are
potentially high-risk but not by virtue of their HIV status, so they
should get PPV. The footnote language is absolutely word for word out of
approved statements, except for rotavirus, which is a little
different.]{.mark}

[The vote is whether to approve the immunization schedules for both age
groups and, as new ACIP recommendations are made, to incorporate them
into the schedule after publication of provisional or final ACIP
recommendations. The options for rotavirus vaccine language are to adopt
the new language presented above, use exact language from the ACIP
statement, which says to weigh the risk and benefits but it can be
given, or recommend that the vaccine not be administered until safety
and immunogenicity efficacy data are available.]{.mark}

[]{.mark}

## [Discussion]{.mark}

[Dr. Baker thought the comment about exposed and infected children was a
good one, since the rotavirus schedule is to be completed by 32 weeks of
age, before it can be established whether children are infected. In
addition, the first 32 weeks are when CD4 counts are very good. She
favored the implicit recommendation from the rotavirus schedule; it is a
benefit to children in general and why should HIV-infected children get
less benefit than regular children under these circumstances?]{.mark}

[Dr. Gilsdorf brought up her suggestion from the previous day about the
use of the word \"recommended\" in the title because it suggests that
all of the bars represent recommendations from the ACIP. She felt that
there was a difference between a recommendation and support. Dr.
Schuchat clarified that the previous discussion had focused on adults
and that the committee was staying away from recommendations on certain
of the adult vaccines for the HIV-infected population because data were
forthcoming, for example for zoster and HPV. That language is much more
critical for the adults where there is a large HIV-infected population
that is looking for guidance and there are more data available. Dr.
Gilsdorf also noted that the wording for HPV should indicate females
only.]{.mark}

[Dr. Treanor pointed out that when the original rotavirus recommendation
was made, the vaccine had not been used extensively; now that there has
been extensive use of the vaccine without problems, people are more
comfortable. However, regarding the fact that rotavirus disease is not
more severe in HIV-infected children, there is the possibility that
people will conclude that there is no special reason to vaccinate. His
recommendation for the wording would be to just leave out No. 2. Dr.
Baker affirmed that suggestion.]{.mark}

[Dr. Morse asked about the footnote that says only TIV should be used
for HIV-infected persons. Dr. Seward clarified that it was strongly
recommended that their contacts get vaccinated, and they can get LAIV.
Dr. Morse thought that was confusing. His second question was whether
revaccination for PPV should be offered or recommended. Dr. Seward
affirmed that 'offered' was the exact language. The data on safety and
immunogenicity of PCV for children aged 2 to 18 years will be presented
in the fall and if it is voted on, it could change the PCV
recommendation.]{.mark}

[Dr. Sumaya asked whether natural rotavirus infections appear to produce
similar levels of severity in HIV-infected as in non-infected HIV
infants and, if so, that needs to be more clearly stated. Dr. Baker
responded that there are actually not strong enough data to say
anything.]{.mark}

[Dr. Offit from Children's Hospital of Philadelphia emphasized that
rotavirus vaccine is a very highly attenuated strain and a pentavalent
vaccine. It is 1.6 times 10 to the sixth platform units per strain and
there are five strains, so 8 million infectious particles are given by
mouth. However, less than 10 percent of children shed and they shed for,
at most, a day or two and in very limited quantities. Oral polio vaccine
or RotaShield shed to a greater extent. This is now the only live
attenuated viral vaccine given routinely to young infants. Typically,
severe combined immunodeficiency disease is not a diagnosis made until
about eight months of age. Since children with SCIDs are clearly getting
this vaccine, it would be interesting to see whether they have increased
or prolonged shedding associated with symptoms.]{.mark}

[Dr. Halsey from Johns Hopkins said he was surprised to hear the
discussion about whether these were recommendations. The public needs
clear recommendations and it would be more efficient than having to
revise other statements.]{.mark}

[Dr. Pickering said the transcript of the rotavirus meeting indicates a
preference that rotavirus vaccine be given to children who are born to
mothers who are HIV exposed. Dr. Parashar added that a number of studies
had looked at viral shedding and immunologic response in HIV-infected
and noninfected children, and the disease severity by a variety of
parameters was identical in both groups. Both mounted equally good
immune responses to natural infection\--about three-fourths of infants
in each group. Shedding was slightly longer in HIV-infected kids, but
most of it was asymptomatic. So they concluded there really was no
difference in the natural history of rotavirus infection in HIV versus
non-HIV kids.]{.mark}

[Dr. Rathore of Jacksonville, Florida suggested that many practitioners,
particularly for HIV-exposed children, may already be using rotavirus
vaccine in these children because his practice had not seen an infected
child in ten years.]{.mark}

**[Vote]{.mark}**

[Dr. Baker made a motion to accept Dr. Seward's recommendation with the
edits that had been discussed. Ms. Stinchfield seconded the motion. Dr.
Gilsdorf asked whether this motion addressed the concerns about the
difference between a full recommendation and support of use. Dr.
Schuchat responded that the distinction was not critical for pediatric
cases, but it was important for adults. Dr. Seward thought that with
live viral vaccines more data might be needed, but not with inactivated
vaccines. An unidentified speaker suggested using a different color,
indicating that the recommendations is being made without data. Dr.
Pickering suggested referring the question back to the respective work
groups for consideration of the wording change in the title.]{.mark}

[Dr. Seward summarized the motion, which was that ACIP approve the
immunization schedule for HIV-infected children \-- exposed and infected
children zero to six years and 7 to 18 years, with the changes in the
footnote as suggested for rotavirus and for influenza and that new ACIP
recommendations will be incorporated into the schedule after publication
of provisional recommendations. Edits include using "exposed or
infected" and specifying females for HPV.]{.mark}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[]{.mark}

**[Adults]{.mark}**

[**Dr. Mootrey** then showed the recommended schedule for HIV-infected
adults. One difference between the children and adults was that there
was already a schedule for children, which just had to be modified. The
adult schedule is a new addition to the guidelines and it has not been
brought to the ACIP adult immunization work group yet. There should be
an updated draft for the opportunistic infections adult work group by
the end of the summer.]{.mark}

[Dr. Morse commented that there should be consistency across the tables
for the "Do not administer" recommendation.]{.mark}

**[[UPDATE ON ROTAVIRUS VACCINES]{.underline}]{.mark}**

**[Dr. John Treanor, ACIP, Working Group Chair]{.mark}**

**[Dr. Umesh Parashar, CDC/NCIRD/DVH]{.mark}**

**[Dr. Penina Haber, CDC/ISO]{.mark}**

**[Dr. Manish Patel, CDC/NCIRD/ISD]{.mark}**

**[Dr. Hector Izurieta, FDA/CBER]{.mark}**

[]{.mark}

[Dr. Treanor announced that he would be rotating off ACIP and wished his
successor luck in chairing the rotavirus working group.]{.mark}

[]{.mark}

**[Safety Monitoring Update]{.mark}**

[**Dr. Haber** provided a summary of RotaTeq vaccine adverse events
reported to VAERS, followed by updates on the Vaccine Safety Datalink
and Merck Phase IV study. From March 2006 up to June 14, 2007, about 6.2
million doses of RotaTeq were distributed. During the same time period,
VAERS received a total of 1,251 reports of adverse events following
RotaTeq vaccination. Of those, 573 (46%) were from RotaTeq given alone,
and 609 (47%) were after the first dose. The most frequently reported
outcomes were diarrhea, vomiting, fever, and hematochezia.]{.mark}

[Of all the reports, 9.4 percent or 117 were confirmed intussusception
reports. Thirty-eight were within 1 to 21 days after vaccination and of
those, 23 were within one to seven days. No intussusception deaths were
reported.]{.mark}

[Dr. Haber described 116 cases in a graph, which showed a couple of
peaks but no major pattern. When intussusception reports are analyzed by
dose distribution of intussusception and by onset interval in days,
there again is no major pattern. After the FDA notice on February 13th,
2007 and following the *MMWR* publication in March, reports to VAERS of
events occurring over 21 days increased, which indicated higher
reporting efficiency to VAERS.]{.mark}

[Overall, the mean age at symptom onset symptom was 23 weeks, the range
9 to 45 days. There was equal distribution between male and female.
Fifty-seven or 49 percent had contrast enema, 32 percent (37) had
surgical reduction, and 16 percent (19) had surgical resection. Two
experienced spontaneous resolution, and for two reports there was no
information.]{.mark}

[Dr. Haber then provided an update on the Vaccine Safety Datalink. From
May 21, 2006 up to June 17, 2007, 68,858 vaccinations were given and
there was no report of intussusception within 30 days post vaccination.
An analysis of distribution by age and dose by age shows that almost 50
percent of vaccinations were Dose 1, and about 30 percent were Dose
2.]{.mark}

[Dr. Haber gave an update on the Merck RotaTeq post licensure safety
study. This is a prospective observational active surveillance. The
study population is a large insured U.S. population with annual birth
cohort of about 100,000, and the planned final study size is about
44,000 vaccinated children. The study plan is to monitor rates of
intussusception and overall vaccine safety, comparing the rates of
several control groups 30 days post vaccination for each dose.]{.mark}

[So far, there have been 7,196 RotaTeq recipients through the third
quarter of 2006. As of December 31st, 2006, there were no cases of
intussusception in RotaTeq recipients, but there were three cases in
controls. The next review will include about 18,000 RotaTeq recipients
vaccinated from February 2006 to December 2006.]{.mark}

[]{.mark}

**[Data Interpretation]{.mark}**

[**Dr. Patel** focused on whether the observed number of cases exceeded
what would be expected to occur by chance alone. Intussusception rates
vary in the first six months of life when the vaccine is being
administered, so age stratification must be taken into account for the
calculations.]{.mark}

[Dr. Patel first talked about the calculations for the 1- to 21-day
window. VAERS received reports of 38 cases of intussusception occurring
within 1 to 28 days of vaccination, whereas approximately 99 cases would
be expected to occur by chance alone, after adjusting for age. The
reporting rate ratio is 0.37, with the upper 95 percent confidence limit
being less than one. Data assumptions are 100 percent reporting
completeness and 100 percent administration of the doses distributed. In
each of the three age groups, the observed numbers did not exceed the
expected.]{.mark}

[For the one- to seven-day window, VAERS has received reports of 23
cases of intussusception, whereas approximately 33 cases would be
expected after adjusting for age. The reporting rate ratio for the one-
to seven-day window was 0.67, which is higher than for the 21-day
window. However, the upper 95 percent confidence limit was 1.08. Within
each of the three age strata, observed numbers did not exceed the
expected, but for the 6- to 14-week age group, the number of observed
cases was the same as the expected number.]{.mark}

[Most of the RotaShield action occurred during the first week of
vaccination with Dose 1. For Dose 1 of RotaTeq, in total, there were 12
cases observed in VAERS after Dose 1 and one would expect approximately
12 background cases within seven days of vaccination using the same 100
percent assumptions. With RotaTeq, it appears that Dose 1 is generally
being administered according to the ACIP recommendations, at 6 to 12
weeks of age. The VSD data show that 93 percent of the doses were
administered in the 6- to 14-week age group and the majority of the Dose
1 cases were also in that age group (10 of the 12 cases). Only two cases
occurred in the second age group (15- to 23-weeks).]{.mark}

[The RotaShield Dose 1 experience was quite different: 80 percent of the
reported VAERS cases for RotaShield were after Dose 1, suggesting a
clustering effect after Dose 1, as opposed to RotaTeq, where only 34
percent occurred after Dose 1. Eighty percent of the RotaShield Dose 1
was administered to children older than 90 days or 12 weeks of age,
whereas only 7 percent of the RotaTeq in VSD has gone to children over
90 days old.]{.mark}

[The nationwide case-control study for RotaShield revealed a 37-fold
risk for Dose 1 within three to seven days of vaccination, whereas no
similar signal has been seen with RotaTeq yet.]{.mark}

[An important question is, of all the cases that are actually occurring
within 1 to 21 days of vaccination, how many are being reported to
VAERS? Looking at all intussusception cases reported to VAERS by onset
month, two-thirds were outside the 1- to 21-day window, which is when
vaccine is unlikely to be biologically linked to intussusception. The
FDA notification in February did stimulate reporting, but most of the
reports in the two months since the FDA notification were also outside
that 1- to 21-day risk window, which suggests that reporting efficiency
is high for the first 21 days of vaccination.]{.mark}

[A second data assumption has to do with vaccine administration, and the
question is, what proportion of the doses that are distributed is
actually being administered? RotaTeq has been on the market for
approximately 16 months and two factors suggest favorable vaccine
uptake. One is that the manufacturer has been distributing 400,000 to
600,000 doses of vaccine per month for the past eight months and the
other is that the VFC contract now has been in place for about a year.
The National Immunization Survey after RotaShield showed that 66 percent
of the vaccine doses distributed were actually administered during the
nine months it was on the market.]{.mark}

[In order to do the sensitivity analysis, the assumption was that
reporting completeness was around 75 percent and that 75 percent of the
doses distributed were actually administered. With these assumptions,
the reporting rate ratio is 0.7 for the 1- to 21-day window, and
slightly above 1 for the 1- to 7-day window. But neither of these is
statistically significant. If the reporting completeness was 50 percent
and vaccine administration was 50 percent of the doses distributed, one
would begin to see a signal. For the 1- to 21-day window, the reporting
rate would be 1.47, and for the 1- to 7-day window, the reporting rate
would be 2.6. Despite these assumptions, the reporting rates are still
rather small.]{.mark}

[Looking at all intussusception cases by onset interval in days, more
cases have been reported during Week 1 compared to Weeks 2 and 3. There
are several possible explanations for this clustering effect. One is the
well-known effect of passive surveillance of adverse events, where
reporting tends to be better closer to the exposure. Another possibility
is that this clustering could represent a two- to three-fold risk in
Week 1 compared to Week 3. Week 1 clustering could be also a random
event. However, since the number of cases is small by week, one should
be cautious in over-interpreting those data.]{.mark}

[In summary, no intussusception signal has been identified with
post-licensure monitoring for RotaTeq in the U.S. To date, the combined
safety data include the 105,000 doses for the REST clinical trial; about
70,000 doses for the VSD; 7,000 Merck postlicensure doses; and 16 months
of VAERS data, none of which has identified a signal. However, one must
be cautious and continue monitoring because the current data cannot
exclude smaller magnitudes of risk, which would require large sample
sizes. If one wanted to exclude a five-fold risk in the first week of
vaccination, for example, one would need follow-up data on nearly
130,000 vaccinees. However, to exclude a two- or three-fold risk, follow
up data for one week on 400,000 to 1.3 million vaccinees would be
needed. Even a case-control study would be fairly cumbersome to rule out
such a magnitude.]{.mark}

[To place this risk in perspective, if there was a two- to three-fold
risk after Dose 1 and the entire U.S. birth cohort of 4 million were to
receive that dose, one would see approximately 25 to 50 additional cases
per year. In contrast, approximately 50,000 to 70,000 rotavirus
hospitalizations would be prevented and possibly 20 to 60 deaths from
rotavirus.]{.mark}

[To reiterate the conclusions from the previous ACIP meeting in February
and the most recent *MMWR,* the observed reporting rates of
intussusception do not appear to be greater than what would be expected
to occur by chance alone. Nonetheless, these data must be interpreted
with the limitations of the passive surveillance system in mind. Ongoing
monitoring will be crucial, particularly for Week 1 after vaccination,
where there may be a clustering effect. Finally, it will be important to
continue to follow VSD and Merck post-licensure cohorts, because a
larger cohort would be needed to exclude smaller risks.]{.mark}

[]{.mark}

**[RotaTeq and Kawasaki Disease: Pre- and Post-Licensure
Experience]{.mark}**

[**Dr. Izurieta** presented data from a study done by a number of
investigators and groups, including the CDC, the Vaccine Safety Datalink
group and the FDA. As background, he explained that the original
FDA-approved label did not include Kawasaki disease cases. In the
original license application were three cases in the vaccine group, and
zero in the placebo group. In the four-month safety update, there were
five in the vaccine group, and zero in the placebo group. Following an
inquiry from the Swiss regulatory agency, an FDA review of Kawasaki
disease showed a total of five cases in the vaccine group, and one in
the placebo group. The placebo was from Finland, and the vaccine cases
were all from the same center in the U.S. None were of Asian descent.
All cases were between 12 and 22 weeks of age and all, except for the
placebo, had received other concomitant childhood vaccinations. All but
the placebo case completed the series of three doses of vaccine.]{.mark}

[When the label revision was made in 2007, Kawasaki disease was reported
among the serious adverse events. For each dose in the Phase III
clinical trial, infants were followed for up to 42 days. Kawasaki
disease was reported in 5 of 36,000 vaccine recipients and 1 of 35,000
placebo recipients. The difference was not statistically
significant.]{.mark}

[Regarding the post-marketing experience, there were reports of Kawasaki
disease, but this does not mean there is or is not an association. No
changes were made in the indications, warnings or precautions regarding
the use of this vaccine.]{.mark}

[In the U.S., Kawasaki disease is the leading cause of acquired heart
disease in children, with over 4,000 cases every year. Almost 80 percent
of these children are under five years of age. The incidence in children
under five, as reported by Dr. Belay in a 2000 *Pediatric Infectious
Disease Journal* article, was between 9 and 19 per 100,000 per year.
Recent unpublished data from the Kids Inpatient Database for 2003 showed
an incidence of 21 per 100,000 for all children under one year of age
and 11 per 100,000 per year for children under six months of age. Data
are missing from 20 percent of the children for specific age in months,
so the 11 per 100,000 for children under six months of age could be
underestimated.]{.mark}

[The disease has not been reported in association with vaccinations, but
in 1983 Japanese investigators reported finding rotavirus particles or
capsomers in 29 of 39 (74%) stool specimens obtained within a few days
of admission for Kawasaki disease to a Tokyo hospital. These patients
did not necessarily have gastrointestinal symptoms. In the control
group, which did not have Kawasaki, the rates of finding rotavirus
particles were much lower. There are no confirmatory studies in the
literature.]{.mark}

[Again with regard to the postmarketing experience, there were four
reports to VAERS following RotaTeq vaccination as of June 19, 2007.
Three were received before the FDA notification and one after
notification.]{.mark}

[Approximately 6 million RotaTeq doses had been distributed in the U.S.
of June 6, 2007, therefore the reported rates from the passive
surveillance system are, in fact, lower than what would have been
expected. This is subject to the limitations of any passive surveillance
system, including VAERS. In addition, providers may not associate
Kawasaki disease with vaccines and will not necessarily report
them.]{.mark}

[Of the four suspected Kawasaki disease cases identified in VAERS, one
was a female of Korean descent, who was almost three months old at first
dose. She had some symptoms, but not enough to be considered classic
Kawasaki disease. The patient was treated by a well-known Kawasaki
expert from Hawaii.]{.mark}

[The second case was a black Hispanic from Texas, almost three months
old as well. For the first dose, there was a three-day interval between
vaccine and onset of symptoms. This patient had all the classic symptoms
for Kawasaki except adenopathy, and also had coronary ectasia. The
patient was treated by intravenous immunoglobulin.]{.mark}

[The third case was from North Carolina, a six-and-a half-month old,
with some classic symptoms after the third dose. But the conjunctival
injection was yellowish, and the patient was diagnosed originally as
having a bad rash. It is not known whether this case will be considered
confirmed or not.]{.mark}

[Information on Case No. 4 is incomplete. The report is for a male from
California, five months of age, with onset 14 days after vaccination.
The medical chart has not been received. All four cases described
received other childhood vaccines as well.]{.mark}

[There has been an ongoing review of all suspected Kawasaki disease
reports to VAERS since it started in 1990. Out of 81 suspected Kawasaki
cases after all vaccines, 44 were from the U.S. Of those 44, 19 were
among children less than a year old, and 13 were under 16 months of age.
Again, this does not mean they are confirmed Kawasaki disease or that
they are causally associated with vaccination.]{.mark}

[The CDC\'s Vaccine Safety Datalink study data come from six of the VSD
sites. There was one unconfirmed Kawasaki disease case, meaning no chart
review was made, out of over 68,000 doses of vaccine. This was within
the expected rate, which would have been around two cases. VSD has
agreed to incorporate Kawasaki disease into the ongoing Rapid Cycle
Analysis of RotaTeq adverse events, as they have done with
intussusception.]{.mark}

[Merck has provided preliminary data from their observational Phase IV
study. As an agreement for licensure, They agreed to an approximately
44,000 study population, and Kawasaki is incorporated. So far, for the
primary analysis window of 30 days after vaccination, no Kawasaki
disease or vasculitis cases have been found in the 7,000 RotaTeq
vaccinees or in the 14,000 concurrent controls.]{.mark}

[In summary, the signal from the pre-licensure clinical trials is now
captured in the label. The Kawasaki reports in VAERS are within what
would have been expected, but risk cannot be excluded. The ongoing
observational studies from the VSD and the Phase IV show reassuring
data, but they are limited because of insufficient power. One will have
to wait until these studies progress to be able to reach conclusive
results. At this time, there is no cause-and-effect relationship
established between Kawasaki disease and RotaTeq or any other vaccine.
FDA, CDC, and Merck will continue to monitor the safety of RotaTeq
vaccine using VAERS, VSD, and the Merck Phase IV data.]{.mark}

[]{.mark}

## [Discussion]{.mark}

[Dr. Baker asked whether fever was part of the criteria for reporting
the second case. Dr. Izurieta replied that the patient had fever for
five days. Dr. Baker then asked whether all four patients had cardiac
echoes and when. Dr. Izurieta replied that the Texas case did. Dr. Baker
noted that coronary ectasia was one of those things that may resolve.
Dr. Izurieta replied that sometimes there is no evidence of ectasia or
the evidence comes later and then resolves if the patient is treated
early.]{.mark}

[Dr. Baker then asked if other etiologies were excluded in the chart
reviews. Dr. Izurieta replied there was not enough information on all
the VAERS cases. The case from North Carolina had an alternative
diagnosis and the case from Hawaii also had otitis. Only the Texas case
was really classic. Dr. Baker said that it was very difficult to
distinguish Kawasaki from certain viral etiologies, especially in
children under six months of age. Even classic cases may have an
alternative infectious disease diagnosis. On the other hand, those are
the patients more likely to have an atypical presentation of Kawasaki
disease where the physician may not make the diagnosis. This is a very
complex association, so it is good that the rapid cycle safety analysis
will be performed.]{.mark}

[Dr. Abramson confirmed that children less than six months of age more
often than not have atypical Kawasaki and those who really have Kawasaki
disease also have a higher incidence of coronary aneurism. He felt it
was imperative to look for those children with the atypical Kawasaki,
even though it might require outside expertise.]{.mark}

[Dr. Gentsch emphasized the importance of standardizing case definitions
for adverse events because, unlike efficacy, safety cannot be measured
directly. It can only be inferred indirectly from measuring multiple,
different adverse events. Without standardization, there is a lot of
heterogeneity and lost data. He added that pre-licensure safety
processes can be improved or standardized using lessons learned from
RotaShield, where there was a similarly small number of events\--about
five in the vaccinated and one or two in the unvaccinated placebo group.
They did a simple 2-by-2 chi square, and the P value was not
significant. But some of those five cases were clustered around the same
time. So a person-time analysis, while not statistically significant,
would have been closer to significance. If a person-time analysis was
not taken into account in the pre-licensure data, it should be in the
future.]{.mark}

[Dr. Pickering asked whether the three cases for which data were
available were already symptomatic when immunized. Dr. Izurieta replied
that one had what appeared to be a bad rash, onset date unknown, but all
of the other symptoms appeared after vaccination, from a few hours up to
Day 14 in Case No. 4.]{.mark}

[Dr. Iskander clarified that VAERS specifies onset as the first symptom,
whereas the standard criteria for Kawasaki define it as the onset of
fever. Dr. Slade added that one child had an onset of fever at 12 hours
after vaccination, but none were symptomatic at the time of
vaccination.]{.mark}

[Dr. Gellin asked what it takes to get something included in the label
initially. He also wondered how robust the Kids' Inpatient Database
(KID) was. Dr. Houn replied that the adverse reaction section of the
label was governed by 21 C.F.R. 201.57(c)(7), which says that adverse
reactions identified for clinical trials, especially those with
significant clinical implications, must be supplemented with additional
details, such as frequency or nature.]{.mark}

[Dr. Iskander said KID more typically uses either the VSD or the HCUP
(Healthcare Utilization Program) databases, but they are happy to work
with any and all databases that provide reasonable background
rates.]{.mark}

[Dr. Abramson asked whether there would be a study design to compare
those who get every immunization but rotavirus with those who get every
immunization including rotavirus. Dr. Gargiullo replied that Ermias
Belay was planning to look at all cases of Kawasaki syndrome going back
to 1992 and one of the hypotheses would be live vaccine versus
inactivated.]{.mark}

## [[UPDATE: HPV VACCINES]{.underline}]{.mark}

## [Dr. Janet Gilsdorf, Chair, HPV Working Group]{.mark}

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

**[Dr. John Iskander, CDC/ISO]{.mark}**

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

[]{.mark}

##  [Dr. Gilsdorf reviewed the activities of the working group to date. In June 2006, the ACIP voted on the recommendations for the quadrivalent HPV vaccine. These provisional recommendations were available on the Web in July 2006, and the HPV vaccine official statement was published in the *MMWR* in March 2007. The recommendations have since been adopted by a number of other collaborating organizations.]{.mark} 

[The working group has continued to meet monthly to review the bivalent
HPV vaccine for safety, immunogenicity, and primary and secondary
endpoints. The GSK bivalent vaccine BLA has been submitted to the FDA,
so the working group has also considered future recommendations to be
addressed with the predicted licensure of the bivalent vaccine.]{.mark}

[]{.mark}

**[Post Licensure Vaccine Safety Data]{.mark}**

[**Dr. Iskander** provided an overview of postlicensure safety
surveillance for Gardasil, the first U.S. vaccine licensed for human
papillomavirus, and summarized available data from the Vaccine Adverse
Event Reporting System and the Vaccine Safety Datalink.]{.mark}

[Gardasil is an inactivated vaccine, which was licensed by the FDA in
June 2006 with an age indication of 9 to 26 years old and was
subsequently recommended by the ACIP for routine use among 11- to
12-year-old females. General safety data were collected from almost
12,000 vaccine recipients in pre-licensure trials, and more detailed
safety data were obtained from a subset of over 5,000 girls and women.
Adverse reactions noted more commonly among vaccine recipients compared
to placebo were injection-site pain, swelling, and erythema. Serious
adverse events were rarely reported during pre-licensure trials. Among
the ten deaths that occurred among Gardasil recipients, cause of death
varied and did not appear plausibly related to vaccination. A total of
four thromboembolic events were reported among vaccine recipients and
six among placebo recipients. There was one fatality in each study
group. Both involved oral contraceptive use, a known risk factor for
thromboembolism.]{.mark}

[Post-licensure safety data primarily focused on VAERS reports of
commonly reported as well as serious adverse events, as defined in the
Code of Federal Regulations. Reports involving population subgroups of
special interest were analyzed separately. The data presented
encompassed the first 11 months of the U.S. experience with Gardasil.
Distribution data were obtained from the vaccine\'s manufacturer,
Merck.]{.mark}

[The vast majority of VAERS reports involved females and 70 percent
covered the indicated age range of 9 to 26 years. Nearly 90 percent of
reported events concerned Gardasil used as a single vaccine. Most
reported adverse events that specified dose number followed the first
dose in the series, however a substantial minority did not indicate the
dose number. Reports to manufacturers, which typically originate from
healthcare providers, make up the majority of reports to VAERS.
Following a pattern typically seen within VAERS, a substantial
proportion of reported adverse events begin on the day of or within a
few days following vaccination. The most commonly reported events
following Gardasil were fever, dizziness and loss of consciousness, also
coded as syncope. Reports typically involved more than one adverse
event, but only 5 percent of all reports were classified as
serious.]{.mark}

[Dr. Iskander then presented clinical details of four deaths following
Gardasil. Case No. 1 was originally reported as being due to influenza A
virus infection. Case No. 2 involved preliminary embolism in an oral
contraceptive user. For Case No. 3, no additional medical records or
clinical information were provided to VAERS, despite multiple attempts
at follow-up. Case No. 4 involved laboratory-confirmed influenza B virus
infection along with MRSA infection and has been reported to the
national surveillance system for pediatric influenza-associated
deaths.]{.mark}

[Among 13 Guillain-Barre syndrome reports, nearly half have involved
co-administration of meningococcal conjugate vaccine (Menactra®). Only
two GBS reports that meet the Brighton Collaboration case definition
have followed Gardasil given as a single vaccine with symptom onset
within six weeks following vaccination.]{.mark}

[Eleven serious reports have involved syncope, all occurring within ten
minutes of vaccination. There have been two documented instances of
intracranial hemorrhage and three non-serious reports of confirmed nasal
fractures. (ACIP recommends a 15-minute waiting period following all
vaccines. Also, syncope is a common condition with a variety of triggers
among young adults.)]{.mark}

[Two additional reports involved thromboembolism. Case No. 2 involved
multiple risk factors for thromboembolism, including a medical one of
OCP use, an environmental one of air travel, and multiple documented
genetic risk factors. Incidence of thromboembolism in OCP users varies
across studies. Risk increases with age and smoking and is also higher
during initiation of medication use, regardless of age.]{.mark}

[VAERS reports among preadolescents involved commonly reported local and
systemic non-serious events. The one report of Stevens-Johnson syndrome
was poorly documented.]{.mark}

[Through the end of March 2007, more than 5 million doses of vaccine
have been distributed in the U.S. Age-specific dose-distribution data
are not available. Within the Vaccine Safety Datalink, three-quarters of
vaccine use has occurred among females under age 18. Safety endpoints
being monitored through rapid-cycle analysis include a range of events
identified through prelicensure study and/or events that commonly occur
among the target age group for this vaccine. The quadrivalent HPV
vaccine is now covered under the Vaccine Injury Compensation
Program.]{.mark}

[ The vaccine safety data presented should be considered as one of a
variety of sources of post-licensure surveillance for this vaccine.
VAERS data may be available more rapidly, but is subject to data quality
and other concerns. CDC will continue to collaborate with FDA, the World
Health Organization, and other public and private entities on
post-licensure surveillance and communication activities.]{.mark}

[]{.mark}

**[Efficacy and Safety Data -- Bivalent HPV Vaccine]{.mark}**

[**Dr. Dubin** presented the results from an interim analysis of GSK's
largest single efficacy study, referred to as HPV-008. The GSK cervical
cancer candidate vaccine contains HPV 16 and 18 virus-like particles, 20
micrograms of each VLP type, and is adjuvanted with AS04 adjuvant. The
AS04 adjuvant was selected because its use resulted in higher levels of
immunogenicity when compared to an aluminum hydroxyl adjuvant.]{.mark}

[Based on these early results, GSK initiated a rather large Phase III
development program that included immunogenicity and efficacy studies.
The immunogenicity studies take data from the efficacy studies been
conducted in women between the ages of 15 and 25 years, and then extend
that through immunogenicity bridging to younger girls and women over the
age of 25 years. The first efficacy study, HPV-001, has been reported on
extensively. A second study called HPV-007 has now followed women in a
blinded fashion through five and a half years following receipt of the
first dose of vaccine.]{.mark}

[There are two other efficacy studies. One is being conducted in Costa
Rica by the U.S. National Cancer Institute, and that has approximately
7,500 subjects enrolled; the other is the HPV-008 trial, the subject of
this presentation. In 2006, GSK started another efficacy study, which
has enrolled over 5,700 women over 25 years of age.]{.mark}

[Results from previous studies have shown that the GSK candidate vaccine
is generally well tolerated and is highly efficacious in preventing HPV
16 and 18 endpoints; it was up to 100 percent effective in preventing
CIN lesions and persistent infections associated with HPV 16 and 18 in
fully vaccinated women and also prevented abnormal cytologies in women
in these studies.]{.mark}

[The previous efficacy study presented primarily assessed the vaccine in
women who were screened and were naïve to oncogenic HPV types at study
entry. In the older studies protection or cross-protection has been
observed against incident infection with a number of HPV types that are
phylogenetically related to HPV 16 and 18, including types 45 and 31,
the third and the fourth most common types associated with cervical
cancer. Immunobridging studies have also demonstrated good
immunogenicity of the vaccine in younger women down to the age of ten
and in women over 25 years of age, with titers in the range associated
with protection in the long-term follow-up study.]{.mark}

[The recently conducted HPV-008 study enrolled 18,644 unscreened women
age 15 to 25 in North and South America, Europe, and the Asia-Pacific
region, including Australia. The cohort included women with current or
prior oncogenic HPV infections. This broad, unscreened population was
thought to represent the kind of target population the vaccine
ultimately will be used in.]{.mark}

[Women were enrolled regardless of baseline cytological abnormalities.
Many were infected with oncogenic HPV and many of these were non-vaccine
types, although there were some with vaccine types as well. The interim
analysis only excluded women found to have high-grade cytology
abnormalities at the entry visit. It included all events reported in
women who have received at least one dose of vaccine.]{.mark}

[Regarding baseline characteristics, 90.5 percent of women had normal
cytologies and the rest had abnormal cytologies, the majority of which
were low grade. The half a percent of women with high-grade cytology
abnormalities were immediately referred for colposcopy. Among women with
normal cytologies at entry, about 15 percent had high-risk HPV, but
women with low-grade cytology abnormalities or high-grade cytology
abnormalities had progressively increased risk of having oncogenic HPV
infection at entry; 91 percent of women with high-grade cytologies at
entry were found to have high-risk HPV infection.]{.mark}

[The women enrolled in this double-blind study were randomized one to
one. The control vaccine was an adapted formulation of hepatitis A
vaccine given on a three-dose schedule, which visually appeared
identical to the active vaccine under investigation. Ten visits were
scheduled over a 48-month period of time. The three-dose schedule was
administered at zero, one, and six months. Blood samples were collected
periodically for serology and cervical samples were collected at
six-month intervals. The cervical samples were routinely tested for HPV
infection and also used to assess cytologies. Management of women with
abnormal cytologies was according to a prespecified algorithm.]{.mark}

[The mean follow-up time when the interim analysis was triggered was 15
months following receipt of the first dose of vaccine. This is a
relatively early time point in the planned longitudinal follow-up, which
will extend through about 48 months.]{.mark}

[When the women with high-grade cytology findings and those who were
missing cytologies were eliminated, a total of 18,525 women remained for
evaluation of efficacy. Immunogenicity was assessed randomly in a
pre-specified subset of subjects that was representative for the regions
participating in the study.]{.mark}

[The primary endpoint of the study was to assess efficacy of the vaccine
and the prevention of histopathologically confirmed CIN2+ associated
with HPV 16 or 18 in the cervical lesion. Diagnosis of CIN2+ was
confirmed by a consensus-panel diagnosis, using three independent
histopathologists who had been trained to evaluate these lesions. This
was separate from the routine panel that assessed the results in a
real-time frame to help guide subject management.]{.mark}

[The methodology used to detect HPV 16 and 18 DNA in the lesion involved
the use of a broad-range consensus primer system, referred to as the
SPF-10 system, and detection was done by a line-probe assay. This SPF-10
system actually detects 14 oncogenic HPV types\-- 16 and 18 plus 11
nonvaccine types, which were routinely evaluated in all samples
collected. In addition, type-specific PCR was done for HPV 16 and 18 to
supplement the broad-consensus primer PCR.]{.mark}

[A sample was considered positive if HPV 16 or 18 DNA was detected using
either of the two methods. Women who were HPV-DNA negative and
sero-negative were assessed at study entry in the primary endpoint
analysis. If a woman was HPV 16 DNA positive or seropositive at entry
and subsequently developed an HPV CIN2+ lesion, she was not counted in
the final efficacy evaluations. However, if she developed an
HPV-18-associated CIN2+ lesion, she was counted. The use of
broad-spectrum PCR in a population of women that was broadly defined and
included many women with prevalent infections with other types at entry
allowed the study to fully characterize lesions for vaccine and
nonvaccine types.]{.mark}

[The interim analysis was event-triggered, defined as whenever 23 HPV 16
or 18 CIN2+ lesions were detected in the total vaccinated cohort. The
final analysis will also be event-triggered and will generate additional
data on CIN2+ outcomes. GSK intends to continue blinded follow-up for up
to four years.]{.mark}

[A high rate of prevalent HPV infections was observed at study entry,
even in women with normal cytologies. Of the 23 lesions that triggered
the interim analysis, 14 or 61 percent showed more than one HPV type
detected in association with the lesion by PCR. Fourteen of the 23
lesions were derived from infections detected prior to completion of the
three-dose series. The third dose is given at the Month-6 visit, which
means the infections were acquired very early in the trial. The high
rate of multiple infections in CIN lesions was not expected, based on
published natural history literature or vaccination trials, so this was
a unique observation, based on evaluating the HPV types across all
lesions and all subjects in all cytology samples.]{.mark}

[The 23 cases could be described by three patterns of HPV detection in
the lesion and also considering HPV types detected in samples collected
prior to detection of the lesion. The first pattern was a relatively
classic one. These were cases where a single HPV type was found in the
CIN2+ lesion and the same type was found in prior samples. Based on the
well-established association between persistent infection and
development of a high-grade lesion, this pattern of detection seemed
very clear-cut. Nine cases fell into this category. An example is a
woman who, after the Month-12 visit, had a punch biopsy triggered by an
abnormal cytology. The punch biopsy showed HPV 18 in association with a
CIN2+ lesion. This subject had prior infection with HPV 18 at the
Month-6 and Month-12 visit; this is also a fairly classic case.]{.mark}

[The second pattern included cases where multiple HPV types were
detected in the CIN2+ lesion with HPV 16 or 18 infection preceding the
development of the lesion. An example of that pattern is a subject who
had a CIN2+ lesion after the Month-12 visit, with HPV 16 and 51
detected. This subject had a number of HPV types detected at previous
time points, but 16 was detected at the Month-6 and the Month-12 visit,
so it was counted as a case of HPV-16-associated CIN2+. There were 11
similar cases with multiple types in the lesion but a clearer pattern of
prior detection of the vaccine type in preceding samples.]{.mark}

[The third pattern, which was the least common and the most unusual,
included cases with multiple HPV types in the CIN2+ lesion with no prior
detection. There were three such cases. The lesions also contained
additional non-vaccine types, serotypes that were not considered in the
analysis, so the question was, which type was the cause of the
lesion?]{.mark}

[Dr. Dubin discussed three cases to show how lesions were assessed. One
subject had a CIN3 lesion detected by punch biopsy after the Month-12
visit, and HPV 16 and 58 were detected in that lesion. That subject
subsequently had a LEEP, which confirmed the diagnosis of CIN3, but only
HPV 58 was detected in the LEEP and at Month 0, Month 6, and Month 12.
There was no prior detection of HPV 16 in any preceding samples.]{.mark}

[The second case was a woman who developed a small CIN2 lesion with HPV
18 and HPV 58 detected in association with the lesion. A subsequent LEEP
was normal, so the lesion was removed by the punch biopsy. HPV 58 was
detected at entry and at the Month-12 visit; there was no prior
detection of HPV 18.]{.mark}

[In the third case, the subject had a CIN3 lesion with HPV 16 detected
at punch biopsy. She subsequently had a LEEP, which showed multiple
lesions, each of which had HPV 16. HPV 18 was found in a single lesion.
Looking back at the history of this patient, multiple HPV types were
detected, but the only consistent type was HPV 16. There was no prior
detection of HPV 18. This case would not count as a case of
HPV-16-associated CIN2+ in the efficacy evaluation because there was
prior infection, but it would count as a case of HPV-18-associated
CIN2+.]{.mark}

[Another analysis was done to evaluate the efficacy of the vaccine
against lesions considered to be causally associated with HPV 16 or 18.
It considered not only the HPV type detected in the lesion, but any HPV
types found in preceding cytology samples. The use of this algorithm was
based on the well-established association between persistent oncogenic
infections and development of CIN2+ lesions.]{.mark}

[Of the 23 cases detected in the broad analysis, two were in the vaccine
group and 21 were in the control arm, giving a point estimate of vaccine
efficacy of 90.4 percent, which was highly significant. The majority of
these lesions were derived from infections that began prior to
completion of the three-dose series.]{.mark}

[In the three cases where the lesions were not believed to be caused by
the types detected just in the lesions, two were in the vaccine group
and one was in the control arm. This left 20 cases: zero in the vaccine
group and 20 in the control arm. So in this evaluation, vaccine efficacy
was 100 percent, which is highly statistically significant.]{.mark}

[In another analysis, the restriction for subjects to be seronegative
for the type ultimately found in the lesions was removed. This analysis
now considers a broader group of individuals, including those who might
have been seropositive for HPV 16 to 18 prior to vaccination. In the
pre-specified analysis, vaccine efficacy was over 90 percent. In the
analysis that considered not only the DNA detected in the lesion but the
prior samples as well, the analysis that best reflects lesions likely to
be causally associated with HPV 16 and 18, vaccine efficacy was 100
percent. Results from an additional analysis, which included women who
were seropositive for HPV 16/18 prior to vaccination, suggest that
vaccine efficacy is not likely to be impacted by serostatus prior to
vaccination.]{.mark}

[Dr. Dubin then described some efficacy results that looked beyond HPV
16 and 18, based on persistent infection endpoints included in the
interim analysis. Persistent oncogenic infection is well established as
a necessary precursor for the development of cervical cancer. When
multiple types are detected in the lesion, causality must be assessed
related to individual types. This is likely to be a bigger issue with
lesions caused by less frequent types, such as 45 and 31, where
co-infections are quite common. Persistent infection was used because
causal association is not an issue when looking at the virus itself and
it avoids possible confounding effects of multiple types in
lesions.]{.mark}

[Given the timing of the interim analysis, most of the persistent
infections detected began prior to completion of the three-dose series.
To assess a 12-month persistent infection, a woman would have to be
positive at Month 6, Month 12, and Month 18 or Month 12, Month 18, and
Month 24. Very few women had completed the Month-24 visit at the time
the interim analysis was triggered. Over 90 percent of the 12-month
persistent infections were first detected at the Month-6 visit, which
means they began sometime between Month 0 and Month 6. Over 70 percent
of the six-month infections began prior to completion of the three-dose
series.]{.mark}

[In the Phase II program, there was evidence of cross-protection using
an incident infection endpoint, and this cross-protection was against
types 45 and 31, two types closely related to 16 and 18. The interim
analysis of the Phase III trial confirmed this effect using a more
robust endpoint, six-month persistent infection instead of incident
infection. So for types 35 and 41, statistical significance was achieved
using the six-month definition of persistent infection. These two types
are responsible for about 10 percent of cervical cancers. Type 45 is the
third most common globally, and 31 is the fourth most common, followed
by 33 and 52. Statistically significant protection was also observed
against six-month persistent infection with type 52 and it was close for
type 33, though not achieved.]{.mark}

[Another analysis looked at 12-month persistent infections, but because
of the lower frequency of this endpoint, no assessment could be made on
an individual type-specific basis. For the 12 oncogenic HPV types, other
than 16 and 18, that can be detected with the SPF-10 system, a point
estimate of vaccine efficacy of about 27 percent was observed and was
statistically significant.]{.mark}

[Results showing immunogenicity of the vaccine over a five-and-a-half
year follow-up period have been presented previously. The interim
analysis assessed immunogenicity over a 12-month follow-up period, and
found that the vaccine was highly immunogenic for the HPV 16 and 18
components. Vaccine and immune response were also assessed in subjects
who were initially seronegative and seropositive for the vaccine types
being evaluated. There was no real difference in immunogenicity. In
fact, when looking at earlier Phase II studies, the only difference was
that seropositives achieve a higher immune response earlier, but the
plateau is essentially the same regardless of serostatus.]{.mark}

[Lastly, Dr. Dubin covered some of the safety evaluations. There was a
very high level of compliance with completion of study visits and it was
comparable between the two groups. There were very few dropouts related
to adverse events, and this was also well balanced between the treatment
groups. There was no difference in the number of events that led to
dropout, and there were many other reasons for subjects dropping out of
the study, mostly migration from the study area.]{.mark}

[Adverse events reported during a 30-day period following each dose of
vaccine were categorized as local injection-site symptoms, general
symptoms, and combined symptoms. The vaccine induced a somewhat higher
rate of local injection-site symptoms \-- pain, redness, and swelling
\-- compared to the control used. General symptoms were more comparable
between the two groups, with slightly higher rates in the HPV group
compared to the control. There was no increase in local or general
symptoms with subsequent doses, and the majority of these reports were
low-grade and transient events.]{.mark}

[The reactogenicity profile of the vaccine did not result in any
differential compliance with receipt of the second and the third dose,
which indicates that the vaccine is well tolerated from the perspective
of the subject. All events following each dose of vaccine were
stratified by initial serostatus or DNA status and no differences were
seen in the reactogenicity pattern, depending on whether subjects were
naïve to the vaccine types, seropositive, or DNA positive to one or both
of the vaccine types. The safety profile appeared to be quite
comparable.]{.mark}

[Another analysis considered less frequent events. Data on symptoms were
solicited very proactively for the 30-day period following each of the
three doses. Medically significant events, defined as conditions that
prompted an emergency room visit or a physician intervention, new onset
of chronic diseases and new onset of autoimmune diseases, were actively
solicited throughout the entire duration of the trial. There was no
difference in the proportion of subjects reporting any of these events.
Serious adverse events were reported over the duration of the trial
without any time restriction; both the proportion of subjects reporting
serious adverse events and the number of serious adverse events reported
were quite similar in the two groups.]{.mark}

[Pregnancy outcomes were assessed as one of the important safety
measures, even though there were contraindications to pregnancy in the
vaccination phase of the protocol. The rate of specific pregnancy
outcomes was well balanced between the two groups.]{.mark}

[This is the largest vaccine study conducted to date and it has helped
to characterize the natural history of HPV in association with multiple
types detected in lesions. With the methodology that will be used to
look at lesions that develop in vaccinated women in a post-licensure
setting, this will be important in trying to better understand causal
association with vaccine and non-vaccine types.]{.mark}

[This study has confirmed a high level of protection against HPV 16 and
18 CIN2+ lesions in a broadly defined cohort of women. The vaccine
efficacy estimate is 90 percent considering any CIN2+ lesions with HPV
16 or 18 detected and 100 percent against lesions where HPV 16 and 18
were likely to be causally associated with the lesion. There was a high
level of vaccine efficacy regardless of initial HPV 16/18 serostatus,
which will be important as use of the vaccine is considered for
non-naïve women. The majority of endpoints were derived from infections
detected prior to completion of the three-dose series, which suggests
that the onset of vaccine effect may actually begin prior to completion
of the full three-dose series.]{.mark}

[The HPV-008 study extends some previous preliminary evidence of
cross-protection. There is evidence of efficacy against HPV 45, 31, and
52, using a six-month persistent infection endpoint. Efficacy is also
seen against 12-month persistent infection in an analysis that considers
a combination of 12 non-vaccine types. Persistent infection is an
important endpoint in assessing these other types because the analysis
is not confounded by the potential for multiple types detected in
biopsies. Finally, the study confirmed that the vaccine is highly
immunogenic and generally well tolerated.]{.mark}

[]{.mark}

**[HPV Vaccines: Future Recommendation Considerations]{.mark}**

[**Dr. Markowitz** provided information on distribution, post-licensure
monitoring, and state legislative action, as well as the next issues for
the ACIP consideration related to HPV vaccine. The ACIP made its
recommendations a year ago, followed by a VFC vote, recommendations on
the Web in July and the VFC contract in October. The vaccine was
included in the National Injury Compensation Program in February, and
the ACIP statement was published in March. Through March of 2007, about
5 million doses have been distributed, 49 percent of that through the
CDC contract and 51 percent non-CDC. By April 2007, all states had
purchased vaccine for the public sector.]{.mark}

[Monitoring includes post-licensure safety monitoring, vaccine coverage,
and disease impact. Merck has an extensive post-licensure safety program
as part of their agreement. They will be doing a post-marketing study in
a managed-care organization. They also have a vaccine pregnancy registry
in which about 300 women have been enrolled. That annual report will be
analyzed and could be presented to ACIP at a later date. A variety of
safety studies are ongoing through the Nordic cancer registry and those
could also be presented.]{.mark}

[Regarding coverage, a variety of data will be available. Some are in
the traditional vaccine coverage surveys, but information on HPV vaccine
has also been included in other national surveys and those data will
become available. The teen module of the National Immunization Survey
was conducted in the fourth quarter of 2006 and will be repeated in the
fourth quarter of 2007. This is a random-digit dialing telephone survey
of parents, with provider check for verification of immunizations.
Funding was just received to expand this in 2008 to provide
state-specific estimates. The adult module is being conducted now (May
through August), and the first data will be available in the fourth
quarter of 2007. That is also a telephone interview, but with no
provider check for verification of immunization status. The National
Survey of Children\'s Health, which is ongoing, will provide national as
well as state-based estimates. There are about 92,000 children in that
sample and data are based on parental recall only.]{.mark}

[There has been substantial media attention around HPV vaccine
legislation. As of June 2007, legislation has been introduced in 41
states, and in 11 states bills have been signed into law. The vast
majority of these laws are about education related to HPV and HPV
vaccine; some are related to funding and insurance to cover HPV vaccine.
Twenty-four states have introduced legislation specifically to mandate
HPV vaccine for school entry. In Texas, there was an executive order for
a middle-school vaccination requirement, which was overridden by the
legislature. In Virginia a mandate did pass that requires HPV vaccine
for girls entering grade six, but there are very broad exemptions. In
North Dakota and New Hampshire, legislation has been passed to allocate
funds to provide vaccines at no cost to females 11 to 18 years of
age.]{.mark}

[There are four major upcoming issues for ACIP: considerations regarding
the bivalent HPV vaccine; issues related to having two HPV vaccines on
the market; additional data from the quadrivalent and bivalent vaccine
trials that may impact recommendations in the coming years; and
considerations that were not included in the first ACIP
statement.]{.mark}

[Information about the bivalent vaccine was presented earlier. The BLA
submitted to FDA in March of 2007 included data on females 10 to 55
years of age. The FDA decision would be in January 2008 at the earliest.
If the vaccine receives an indication for currently recommended age
groups, the work group and ACIP will need to review the clinical trial
data on efficacy, immunogenicity, and safety, as well as additional
information on adjuvants, since this is a new adjuvant. If there are
indications for use in older women, the committee will have to consider
recommendations for those age groups. Options include permissive,
risk-based, no recommendation, or some other recommendation. Data on
sexual behavior in the U.S. will be reviewed, from national surveys,
natural history, and HPV incidence data in older women as well as other
information on HPV and cost-effectiveness in this older age
group.]{.mark}

[With two HPV vaccines on the market, there will be considerations and
data needs around the issues of preference and interchangeability. The
work group has started examining whether there are differences related
to protection against HPV 16 or 18 and cervical cancer between the two
vaccines, or differences related to duration of protection,
immunogenicity, or cross-protection. There are differences related to
protection against HPV 6 and 11 related diseases since these types are
included in the quadrivalent vaccine and not in the bivalent vaccine.
Another issue will be cost-effectiveness. Any precedent for how ACIP has
dealt with the preference when making recommendations for other vaccines
will be reviewed. There has been no situation completely analogous to
HPV vaccine that ACIP has had to consider.]{.mark}

[If there is no preference, there will be issues around
interchangeability of doses. At the time of licensure, there will be no
data on interchangeability. If someone starts the series with one
vaccine, the quadrivalent, for example, can she complete her doses with
the bivalent vaccine?]{.mark}

[In terms of additional data, both manufacturers are looking at efficacy
in females older than 25 or 26; safety and immunogenicity;
co-administration with adolescent vaccines; safety and immunogenicity in
HIV-positive women and, from Merck, HIV-positive men. Efficacy trials in
men are being conducted for the quadrivalent vaccine, and both
manufacturers are doing Phase IV and long-term follow-up
studies.]{.mark}

[On-going studies with the quadrivalent vaccine could impact
recommendations. The efficacy trial in women 24 to 45 years of age is
looking at prevention of persistent infection and disease in this older
age group of women. There are also two studies in men; the earliest data
would be available in the third quarter of 2008. If FDA or ACIP require
efficacy data instead of immunogenicity data to consider recommendations
in older women, 2008 would be the time frame, and for recommendations in
males, it would be 2009 or 2010. This depends on when the endpoints
occur because these are endpoint-driven analyses.]{.mark}

[Some issues have come up about considerations not included in the
current statement, such as inadvertent administration of the vaccine by
the subcutaneous route or other special situations related to
pre-existing disease in women.]{.mark}

[Finally, the ACIP work group has talked about ACIP statements for HPV
vaccine, including format. The preference was a new ACIP statement with
information on both vaccines, rather than a separate statement for the
bivalent vaccine. The time line for a new draft statement would probably
be February 2008.]{.mark}

[Future plans for ACIP meetings include further review of Phase III
data, a discussion of the adjuvant, and an update on any new data from
the quadrivalent HPV vaccine in October. Epidemiology of HPV and various
HPV-related outcomes should be addressed, including genital warts and
RRP, followed by discussion of potential recommendations. February would
be the earliest there could be a vote. At that time, cost-effectiveness
data would be reviewed as well.]{.mark}

[]{.mark}

## [Discussion]{.mark}

[ Dr. Gilsdorf asked about the tissue samples obtained by punch biopsy,
cone, or LEEP, and whether the virus was detected by PCR only or also
confirmed by tissue probes. Dr. Dubin replied that the protocol was to
do microdissection of the lesion and then apply PCR on samples derived
from the lesion. One of the ways this is being assessed now is to look
at assays that allow evaluation of gene expression in these cases. The
assay currently being used has type specificity for expression of the
E-4 protein. Analyses done with the E-4 protein immunohistochemical
assay fully support the causal associations made in the study.]{.mark}

[Dr. Gilsdorf asked whether the histochemical data confirmed the PCR
data. Dr. Dubin replied that the study specifically looked at lesions
where HPV 16 or 18 was detected only in the lesion but not in any prior
samples. The available immunohistochemical probes are for HPV 16 and 18,
and those were not detected in the lesions. In other lesions where the
vaccine type detected in the lesion and in the prior cytology samples
were known, the E-4 immunohistochemical signal was consistently detected
in the lesions.]{.mark}

[Dr. Chen commented that it is challenging to sort through a large
number of individual HPV VAERS reports with multiple adverse events when
the staff is limited. At one point, a panel of data safety monitoring
tools was developed to look for new permutations of new adverse events
or new syndromes. He asked whether these tools were being applied to
HPV. Dr. Iskander responded that Dr. Chen was referring to advanced
signal-detection techniques or data mining, as a way of sorting through
very large and complicated databases. A conscious decision was made not
to present that type of data to the ACIP without sufficient background,
but in fact steps are being taken to use both types of analyses. They
are routinely used in joint analyses of VAERS done with FDA and
incorporated into publications. Some of those methods will be brought
before the committee in the future, first in terms of general background
and then incorporated routinely in some of the safety analyses.]{.mark}

[Dr. Abramson asked whether there was any plan to look at the effect of
the new mandate in Virginia, in terms of increasing immunization and
opt-out categories. Dr. Markowitz replied that there was an adolescent
work group at CDC and the issue has been discussed with the Immunization
Services Division. There is also the interesting case of New Hampshire
and other states that have made vaccine available free of charge. CDC is
actively discussing how to evaluate those states that have adopted
either legislation or other implementation measures.]{.mark}

[Dr. Schuchat commented that there was now an opportunity to pitch
state-specific estimates for adolescent coverage through a teen module
at the NIS. There will be an on-going examination of attitudes about
vaccine acceptance in the NIS and also in insurance modules. The plan is
also to collect ongoing information about coverage, acceptability or
safety concerns, and financial patterns.]{.mark}

[]{.mark}

## [[UPDATE: VARICELLA]{.underline}]{.mark}

## [Adriana Lopez, CDC/NCIRD/DVD]{.mark}

[]{.mark}

[**Ms. Lopez** presented results from an investigation of an outbreak of
varicella among two-dose recipients. In the past two years, ACIP has
made new recommendations for varicella immunization. In June 2005, a
second dose of varicella vaccine was recommended in children for
outbreak control, resources permitting. Then in June of 2006, a routine
second dose for all children was recommended, with the first dose given
to children 12 to 15 months of age, the second dose for children four to
six years of age, and catch-up vaccination for all persons over age
six.]{.mark}

[During the fall of 2006, an outbreak of varicella occurred in southeast
Arkansas. When the outbreak came to the attention of the health
department, 31 cases had been reported. Of these, eight were among
two-dose recipients, and all cases were reportedly mild. The outbreak
occurred in an elementary school complex that housed three schools.
School A included pre-K students, School B included grades K through
three, and School C included grades four through six. The same school
complex had experienced an outbreak during January and February of 2006.
During that outbreak, in accordance with the June 2005 ACIP
recommendation, the Arkansas health department set up a vaccination
clinic to help with outbreak control. Approximately 400 students were
vaccinated at that time, and many received a second dose.]{.mark}

[Because cases in this current outbreak included two-dose recipients,
CDC was invited to assist with the investigation. The main objectives of
the investigation were to confirm varicella in cases that had received
two doses and to characterize the vaccine effectiveness among one- and
two-dose recipients, if possible.]{.mark}

[A case was defined using the Council of State and Territorial
Epidemiologists case definition of acute maculopapular vesicular rash
without other apparent cause occurring between September 1 and December
18 among students in the school complex. Disease in vaccinated persons
is generally mild with fewer than 50 lesions, shorter duration of
illness, and atypical appearance with macules and papules and few or no
vesicles. Given the large number of insect bites common to this area, a
person had to have at least three lesions to be considered a case.
Laboratory confirmation of cases was done using PCR to test lesion
specimens and environmental samples and IgM for blood and saliva
specimens.]{.mark}

[Cases among students in the school complex were identified from the
health unit, the school nurse, and a survey that was sent to the entire
school. The survey included questions about vaccination status and
varicella disease history, medical conditions, and screening questions
for rash illness to try to identify mild cases. Parents of case-patients
were contacted and asked about clinical information, medical conditions
that could affect immunity, and medication.]{.mark}

[Varicella vaccination status was verified by reviewing the Arkansas
immunization registry. Alternate sources included paper records at the
local county health department and the parental surveys, if the parent
had provided date of vaccination. Children were considered unvaccinated
if they had received their first dose less than or equal to 42 days
before rash onset. Children receiving their second dose less than or
equal to 42 days before rash onset were considered as having
indeterminate vaccination status.]{.mark}

[The overall response rate from the school-wide survey was 79 percent,
with the response from School C being significantly lower than responses
from Schools A and B. No differences were identified between responders
and non-responders with respect to gender and vaccination status.
However, a difference was found for race/ethnicity, where
African-American children were less likely to respond compared to white
or Hispanic children.]{.mark}

[A total of 85 cases were identified during the outbreak, which lasted
almost four months. Most cases occurred among one-dose recipients, but
two-dose recipient cases occurred throughout the entire outbreak. None
of the cases had more than 250 lesions. The two-dose cases tended to be
slightly milder than the one-dose cases and those with previous disease,
although the difference was not statistically significant. Those with
unknown number of lesions were excluded from this analysis. Similarly,
no statistically significant differences were seen between the one- and
two-dose cases and those with prior disease history with respect to rash
description, median duration of rash, and fever. However, two-dose cases
and those with prior disease tended to have shorter rash duration than
one-dose cases, four and six days, respectively.]{.mark}

[The mild clinical presentation of cases during this outbreak made
diagnosis difficult. Clinical specimens from a lesion and saliva were
collected on the day of rash onset. Twenty-five (29 percent) of the
cases were among two-dose vaccine recipients, with three of them having
either previous or unknown history of disease, for an attack rate of
10.4 percent. A majority (64 percent) of the cases occurred among
one-dose vaccine recipients. Seven of these had previous history of
disease, for an attack rate of 14.6 percent. Lastly, six cases (7
percent) had no history of vaccination, but all had previous history of
disease. Thus, it was not possible to calculate an attack rate or
vaccine effectiveness against no vaccination.]{.mark}

[The overall vaccination coverage with at least one dose in the school
complex was 97 percent, and the two-dose coverage was 41 percent.
Twenty-seven cases had specimens collected for laboratory confirmation.
Six of those had positive results; five specimens were from lesions and
positive by PCR; one from a two-dose recipient, three from one-dose
recipients, and one from an unvaccinated person with history of disease.
The sixth positive result was from IgM from a one-dose
recipient.]{.mark}

[Environmental samples collected from the school, and bedding and
bedclothes from cases were also tested. A set of pajamas from a case
with indeterminate vaccination status was PCR positive. This case also
had a positive lesion specimen. A pillowcase from a one-dose recipient
was also PCR positive. This case did not have clinical specimens for
testing.]{.mark}

[Because there were no cases in persons with no vaccination and no
disease history, vaccine effectiveness was calculated against clinical
varicella using historic attack rates. An attack rate for unvaccinated
of 80 percent was used. The vaccine effectiveness among two doses versus
unvaccinated for this outbreak was 87 percent, with 95 percent
confidence intervals of 80.5 to 91.4. The one-dose versus unvaccinated
vaccine effectiveness was 81.8 percent with 95 percent confidence
intervals from 75.8 to 86.2 percent. Although the two-dose vaccine
effectiveness point estimate was higher than the one-dose estimate, the
confidence intervals overlap.]{.mark}

[Some limitations to this investigation included that there may not have
been sufficient power to detect differences between the one- and
two-dose cases. Misclassification of cases could have occurred because
of the broad clinical definition used, which could have led to false
positives. Similarly, mild disease could have led to false negatives.
Lesion-based laboratory diagnostics were only helpful while transient
rash was still present; it was not possible to confirm any of the cases
reported before CDC\'s arrival. Misclassification of disease history
could have occurred because this was based mainly on parental report.
Response rate was significantly lower among students from School C,
however since vaccination status was obtained from the state registry,
this is unlikely to have affected vaccination coverage and effectiveness
estimates.]{.mark}

[This was one of the largest varicella outbreaks investigated in recent
years, and the first U.S. outbreak reported with a significant number of
two-dose vaccine recipients. Challenges with case ascertainment, because
of the mild presentation of disease, may preclude the evaluation of two-
versus one-dose risk-reduction assessments in outbreak settings.
Moderate two-dose coverage of 40 percent was insufficient to prevent
this outbreak. Additional vaccine-effectiveness studies for two doses
are needed. Lastly, to assess the impact of the routine two-dose
varicella vaccination policy, it will be important to monitor the number
and size of outbreaks as a key outcome.]{.mark}

[]{.mark}

## [Discussion]{.mark} 

[Dr. Gilsdorf asked whether the two-dose failures all received their
vaccine from the same provider and if so, how about vaccine storage. Ms.
Lopez replied that they all received their vaccine at the clinic held in
February of 2006. Handling and storage were evaluated and everything
looked fine.]{.mark}

[Dr. Katz asked why pillowcases and pajamas were cultured. Ms. Lopez
replied that they were trying to see if environmental sampling would be
a good way to diagnose varicella in outbreaks where CDC comes in after
the fact. Dr. Katz asked if there were any data from past environmental
sampling of varicella and Ms. Lopez replied that environmental sampling
had been done during an outbreak in a West Virginia long-term care
facility. The index case was a zoster case, and there were three
varicella cases that occurred subsequent to that zoster case.
Environmental sampling made it possible to link the cases, which all had
a unique strain of varicella.]{.mark}

##  [Dr. Iskander shared a recent observation from VAERS on reports of multiple, small clusters following second doses of varicella vaccine described as "cellulitis". They do not appear to be clustering and may represent provider unfamiliarity with the normal safety profile of the vaccine. The other possibility is that there may be a biologic difference in the reactogenicity of second dose depending on the age at which it is given. Pictures or any other information are being sought that might shed additional light on this emerging clinical observation.]{.mark}

## []{.mark}

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

[]{.mark}

## [CDC]{.mark}

[**Dr. Schuchat** reported that the reorganization of the Coordinating
Center for Infectious Diseases at CDC was approved in March, so the
National Center for Immunization and Respiratory Diseases now has
official status. There is an annual report and a new web site, including
a vaccine component. There is also a new module for adolescent
immunization coverage. An adolescent immunization campaign will be
launched this summer, targeted to parents of 11- to 12-year-old
children.]{.mark}

[]{.mark}

## [CMS]{.mark}

[**Ms. Murphy** mentioned the VFC maximum administration rates and the
fact that she had been receiving many inquiries. She explained that she
is the immunization focal point for Medicaid, but Medicare and Medicaid
are not related and do not always share information, so she would
appreciate being kept in the loop. She formulates answers to letters
that come to her. Because of the publicity that the low VFC
administration rates have been getting lately, the stock answer has
been, \"I can\'t do a thing about it. It\'s all in regulation. It\'s all
in statute.\" If the VFC maximum regional administration rate is to be
changed, states must demonstrate that this needs to be done. When the
discussion started in 2005, she discovered that only five states were
actually paying the maximum rate for Medicaid. Since she has been
working with agencies and associations to work with Medicaid and
individual states, there are now nine states paying the maximum rate for
Medicaid and 12 other states have raised their rates. She urged the
committee to continue working with the state Medicaid agencies and
immunization program agencies to have rates raised to the maximum. If
that can be done, Ms. Murphy can then work with the different
associations to ensure that studies are undertaken in order to show what
is needed to obtain a more equitable rate.]{.mark}

[]{.mark}

## [DOD]{.mark}

[**Dr. Cieslak** first addressed the issue of smallpox vaccine and
contact *vaccinia* in vaccine recipients. After vaccinating for exactly
five years with well over a million recipients, there have been 60
cases, which is an average of one case a month over the life of the
DOD\'s resumption of smallpox vaccination. In March of this year, there
were five cases, but that is probably just a statistical aberration. All
of the vaccine is coming from the same lot and the five cases were
widely dispersed geographically.]{.mark}

[The second issue involved the adenovirus vaccine. The DOD is engaged in
a study of a new bivalent adenovirus vaccine involving Serotypes 4 and
7, which are historically the types that have caused most severe
adenoviral disease amongst military recruits. There is currently an
outbreak of severe adenoviral-14 disease among Air Force basic trainees
at Lackland Air Force Base in San Antonio. The long-term implications
are being studied, i.e., whether this is an aberration or here to stay.
The DOD is also interested in whether the bivalent 4/7 vaccine will
provide any cross-protection against serotype 14 or whether a type-14
serotype might have to be added to a vaccine construct.]{.mark}

[]{.mark}

[**FDA**]{.mark}

[**Dr. Houn** reminded the audience that the sanofi pasteur H5N1
influenza virus vaccine was approved in April. In May, the final
guidance on development of both seasonal and pandemic influenza virus
vaccines was issued. At the May VRBPAC meeting, FluMist was discussed,
as well as the Acambis smallpox vaccine, which was voted by the VRBPAC
to be the first vaccine to have a recommendation for a medication guide.
This is an FDA-approved patient package insert on risks and benefits. It
was also recommended to have a risk-minimization action plan to minimize
identified risks of that vaccine.]{.mark}

[]{.mark}

[**HRSA**]{.mark}

[**Dr. Jevaji** reported that the vaccine autism trial started on June
11^th^ and concluded on June 26th. Three special masters heard the
evidence on a test case. The test case was determined by the
petitioners, and then petitioners and respondents introduced testimony
for the general population, as well a specific causation related to the
test case.]{.mark}

[The inquiries involved a theory that MMR vaccine and
thimerosal-containing vaccines can cause the alleged injury. So far,
5100 thimerosal-related autism claims have been filed with the National
Vaccine Injury Compensation Program, and of these, 4800 cases are
pending. The remaining 300 were either dismissed because of the statute
of limitations or they chose to go to the regular program. Since both
parties responded and the petitioners consented, the hearing can be
accessed online by searching on the web for \"autism and court
hearing.\" Future hearings regarding the autism trial will be heard on
two theories; designation of the test cases will be determined by the
Court and the special masters.]{.mark}

[On February 7th, Representative Dave Weldon, a Republican from Florida,
and Carolyn Maloney, a Democrat from New York, introduced a bill called
the Mercury-Free Vaccines Act of 2007. This bill was introduced to amend
the FDA act to eliminate mercury exposure from the vaccines. The bill
was referred to the Committee on Energy and Commerce.]{.mark}

[On April 20th, the *Federal Register* notice was published announcing
the addition of the meningococcal and HPV vaccines to the list of
vaccines covered by the National Vaccine Injury Program.]{.mark}

[The Statute of Repose for influenza vaccine is coming to an end on June
30, 2007. So far, there have been 117 claims, of which 106 represented
adults and the rest were children under the age of 18 years. The Statute
of Repose is a look-back provision that goes back eight years from the
date the vaccine came onto the table.]{.mark}

[]{.mark}

## [NIH]{.mark} 

[**Dr. Curlin** announced that the *Jordan Report* had finally been
delivered, on the last day of the ACIP meeting. It can be downloaded or
one can get hard copies by emailing Barbara Mulach at NIH.]{.mark}

[]{.mark}

[**NVPO**]{.mark}

[**Dr. Gellin** announced that Angela Shen would be returning from
maternity leave after Labor Day and that Dan Salmon was returning to
NVPO to focus on vaccine safety. The national vaccine plan is in need of
an update and more will be said about that in the future. The adolescent
working group has a paper in the process of being submitted that
highlights the challenges of adolescent vaccination.]{.mark}

[**Dr. Hinman** provided information about the NVAC registries. The
immunization coverage subcommittee of NVAC has led the development of a
progress report on immunization and information systems or immunization
registries. This was approved in February of this year by NVAC and
should be posted on the Web in October or November, and we hope that it
will be published.]{.mark}

[NVAC's target is 95 percent of children less than six years of age
having two or more immunizations recorded in an immunization registry by
the year 2010. As of the end of 2005, it was at 56 percent and at the
end of 2006, it appeared to be about 65 percent.]{.mark}

[Registries are the most developed of the public health information
systems and, perhaps, the only ones that really cross the public
sector/private sector divide. They provide clinical-decision support to
providers in states around the country. They are increasingly containing
information about adults and the majority of registries accept
information on all ages. The majority of pandemic influenza plans
incorporate the use of registries to track immunizations given during
pandemic response. The next step is linking with electronic health
records, which is already being done in a limited number of places. Some
of the major barriers have to do with exchanging information across
state lines, which currently requires setting up individual memoranda of
agreement. Providing long-term financial sustainability for registries
continues to be a problem, but progress is being made.]{.mark}

[]{.mark}

## [[PUBLIC COMMENT]{.underline}]{.mark}

[]{.mark}

[**Mr. Scott Lassiter** said he believed the CDC had misled the ACIP on
thimerosal and that the five oft-quoted epidemiologic studies weren\'t
worth the paper they\'re written on. At the request of Congress last
year, the NIH convened a panel of the top epidemiologists in the country
who concluded that the Verstraaten study had several serious flaws and
that the other studies were even worse. The panel concluded it was still
an open question whether vaccines cause autism.]{.mark}

[According to Mr. Lassiter, internal correspondence obtained by the
Freedom of Information Act indicates that the CDC knowingly manipulated
data that originally showed a connection between thimerosal and autism.
For proof, he suggested reading the web site putchildrenfirst.org, or
reviewing the CDC\'s own e-mails and meeting minutes from that time
period. The hard science in lab and animal research from leading
universities indicates that thimerosal is a dangerous neurotoxin, twice
as potent as methylmercury, and that it causes autism-like behaviors and
white-matter changes in the brain. He reminded the committee of its
responsibility to put children first and urged members to do their own
research.]{.mark}

[]{.mark}

[**Karen Beauvais** spoke on behalf of the National Autism Association
of the greater Atlanta area, consumers of vaccines, and a seven-year-old
boy named Joshua Beauvais who received 277 times over the EPA-allowable
amount of thimerosal in his infant vaccines. Joshua has undergone four
years of very aggressive chelation therapy. He was endoscopied and not
found to have the typical autism-measles hyperplasia, which led to
extensive industrial testing of urinary porphyrins. Joshua is showing
hundreds of times over what he should have for mercury in his body, all
of which is believed to have been from his Hib, his DTaP, and his hep-B
series.]{.mark}

[She read the following from the material data safety sheet for
thimerosal, which is still in influenza vaccine and other vaccines:
\"This substance may be toxic to the kidneys, the liver, the spleen,
bone marrow, and the central nervous system. Repeated or prolonged
exposure to the substance can produce target organ damage. Repeated
exposure to highly toxic material may produce a general deterioration of
the health by accumulation in one or many of the organs.\"]{.mark}

[The work of Amy Tsao indicates that children have sustained DNA damage,
and the material data safety sheet indicates that new genetic defects
are being seen in humans with thimerosal. She implored the committee to
make vaccines safe for all: for pregnant women and for little
children.]{.mark}

[]{.mark}

[As there was no further public comment, the meeting was adjourned at
approximately 1:33 p.m.]{.mark}

> I hereby certify that to the best of my knowledge, the foregoing
> Minutes of the June 27-28, 2007 ACIP Meeting are accurate and
> complete.

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

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

> Advisory Committee on Immunization Practices

Attachment One: List of committee members and liaison members and other
attendees

[]{.mark}

CHAIR

JON S. ABRAMSON, M.D.

Weston M. Kelsey Professor and Chair, Department of Pediatrics

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

EXECUTIVE SECRETARY

LARRY K. PICKERING, M.D.

Senior Advisor to the Director, National Immunization Program

Centers for Disease Control and Prevention, Atlanta, Georgia

ACIP MEMBERS

BAN MISHU ALLOS, M.D.

Assistant Professor, Division of Infectious Diseases

Vanderbilt University School of Medicine, Nashville, Tennessee

CAROL BAKER, M.D.

Professor of Pediatrics, Molecular Virology and Microbiology

Baylor College of Medicine, Houston, Texas

MR. ROB BECK

Palmyra, Virginia

JANET R. GILSDORF, M.D.

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

University of Michigan, Ann Arbor, Michigan

HARRY HULL, M.D.

State Epidemiologist and Director

Minnesota Department of Health, Minneapolis, Minnesota

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

Medical Director, Massachusetts Department of Public Health

Jamaica Plain, Massachusetts

TRACY LIEU, M.D.

Associate Professor of Ambulatory Care and Prevention

Harvard Pilgrim Healthcare and Harvard Medical School, Boston,
Massachusetts

JULIE MORITA, M.D.

Medical Director, Immunization Program

Chicago Department of Health, Chicago, Illinois

DALE L. MORSE, M.D.

Director, Office of Science and Public Health

New York State Department of Health, Albany, New York

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

Clinical Associate Professor of Medicine

University of Washington, Seattle, Washington

PATRICIA STINCHFIELD, NP

Director, Pediatric Infectious Disease and Immunology

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

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

School of Rural Public Health

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

JOHN J. TREANOR, M.D.

Associate Professor of Medicine

University of Rochester, Rochester, New York

EX OFFICIO MEMBERS

NORMAN BAYLOR, Ph.D.

Food and Drug Administration, Rockville, Maryland

JAMES E. CHEEK, M.D.

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

GEORGE CURLIN

Medical Director, National Institutes of Health, Bethesda, Maryland

BRUCE GELLIN, M.D.

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

WAYNE HACHEY, DO, M.P.H.

Department of Defense, Falls Church, Virginia

INDIRA JEVAJI, M.D.

Medical Officer, Division of Vaccine Injury Compensation

HRSA, Bureau of Health Professions, Rockville, Maryland

LINDA MURPHY

Centers for Medicare and Medicaid Services, Baltimore, Maryland

KRISTIN NICHOL, M.D.

Chief of Medicine, VA Medical Center, Minneapolis, Minnesota

LIAISON REPRESENTATIVES

American Academy of Family Physicians

DOUG CAMPOS-OUTCALT, M.D.

University of Arizona, College of Medicine, Phoenix, Arizona

JONATHAN TEMTE, M.D.

Family Practice Residency Program, Madison, Wisconsin

American Academy of Pediatrics

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

Children\'s Hospital of LSU, Shreveport, Louisiana

America\'s Health Insurance Plans

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

Medical Director, Intermountain Healthcare, Salt Lake City, Utah

American College Health Association

JAMES C. TURNER, M.D.

Director, Elson Student Health Center

University of Virginia, Charlottesville, Virginia

American College of Physicians

SANDY FRYHOFER

American Medical Association

LITJEN TAN, Ph.D.

Director, Infectious Diseases, Immunology, & Molecular Medicine

Chicago, Illinois

American Osteopathic Association

STANLEY E. GROGG, D.O.

Oklahoma State University, Tulsa, Oklahoma

American Pharmacists Association

STEPHAN L. FOSTER, Pharm.D.

University of Tennessee, Memphis, Tennessee

Association of Teachers of Preventive Medicine

W. PAUL MCKINNEY, M.D.

Professor and Chief, Division of Internal Medicine

University of Louisville, Louisville, Kentucky

Biotechnology Industry Organization

CLEMENT LEWIN, Ph.D., MBA

Executive Director for Strategic Planning & Intelligence

Chiron Vaccines, Orange, Connecticut

Canadian National Advisory Committee on Immunization

DR. JOANNE LANGLEY, Division of Infectious Diseases, Department of
Pediatrics, Canadian Center for Vaccinology, Dalhousie University, Nova
Scotia, Canada

Healthcare Infection Control Practices Advisory Committee

STEVE GORDON, M.D.

Cleveland Clinic, Cleveland, Ohio

Infectious Diseases Society of America

SAM KATZ, M.D.

Wilbert C. Davison Professor

Duke University Medical Center, Durham, North Carolina

London Department of Health

DAVID M. SALISBURY, M.D.

Director of Immunization, Department of Health. London, UK

National Association of County and City Health Officials

NANCY BENNETT, M.D.

Director, Center for Community Health

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

JEFFREY DUCHIN, M.D.

Chief, Communicable Disease Control, Seattle, Washington

National Foundation for Infectious Diseases

WILLIAM SCHAFFNER, M.D.

Professor and Chairman, Vanderbilt University School of Medicine

Nashville, Tennessee

National Immunization Council and Child Health Program, Mexico

VESTA RICHARDSON, M.D.

General Director, National Center for Health and Infancy and Adolescence

Colonia Merced Gomez, Mexico

National Medical Association

WINSTON PRICE, M.D.

National Vaccine Advisory Committee

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

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

Pharmaceutical Research and Manufacturers of America

DAMIAN A. BRAGA

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

PETER PARADISO, M.D.

Vice President, Wyeth Vaccines, Collegeville, Pennsylvania

Society for Adolescent Medicine

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

Baylor College of Medicine, Texas Children\'s

Hospital, Houston, Texas

Society for Healthcare Epidemiology of America

HARRY L. KEYSERLING, M.D.

Professor of Pediatrics, Emory University, Atlanta, Georgia

Other Registered Attendees

Peter Alberti, Merck & Co.

Christopher Ambrose, Medimmune, Inc.

Dilek Arman, GAZI University, Turkey

Judith Armoni, sanofi pasteur

Jennifer Armstrong, GlaxoSmithKline

Phyllis Arthur, Merck & Co.

Kevin Ault, Merck Vaccine Division

Mutlu Aydingulu, sanofi pasteur, Turkey

Lynn Bahta, Minnesota Department of Health

Yaela Baine, GSK Biologicals

Allyn Bandell, Medimmune

Robert Bargatze, LigoCyte Pharmaceuticals, Inc.

Eliav Barr, Merck & Co., Inc.

Kenneth Barr, National Vaccine Program Office

Joan Benson, Merck & Co., Inc.

Eugenia Barnard, Parent

Guthrie Birkhead, New York State Department of Health

Andrew Bowser, AB Writing & Editing, Inc.

Lynn Bozof, National Meningitis Association

Kimberly Bradley, Merck & Co., Inc.

Esthel Brakel, GlaxoSmithKline, Belgium

Dennis Brooks, Merck & Co., Inc.

Ariel Buda-Levin, SciMed

Delvin Carmel, Wyeth

Donna Cary, sanofi pasteur

Danielle Castellani, Cooney/Waters Group

Dan Pharm Casto, Merck Vaccine Division

Michael Chaney, GA Chapter, AAP

Richard Clover, University of Louisville

Kathleen Coelingh, Medimmune Vaccines

Chis Colwell, Biotechnology Industry Organization

Edward Conner, Medimmune

Lenore Cooney, Cooney/Waters Group

Steinhart Corklin, Merck & Co., Inc.

Mike Corvaia, Balance Medical Staffing

Margaret Cross, Palo Alto Medical Foundation

Christensen Cuculich, Wyeth Pharmaceuticals

Gerard Cunningham, Merck & Co., Inc.

Stephen Dachowski, Merck Vaccine Division

Donald Dalrymple, Dalrymple & Associates, LLC

Adrian Dana, Merck & Co., Inc.

Ana Dayton, Constella Group

Michael Decker, sanofi pasteur

Shelley Deeks, Public Health Agency/Immunization and Respiratory
Infections Division

Laurence N. DeMoer, GlaxoSmithKline, Belgium

Liad Diamond, GSK Biologicals

Richard Dinovitz, Wyeth Pharmaceuticals

Jagdeep Dosanjh, GlaxoSmithKline

Kelley Doughtery, Merck & Co., Inc.

Gary Dubin, GlaxoSmithKline

Colleen Duffy, Merck Vaccine Division

Frank Dutko, Merck & Co., Inc.

Sal Espinosa, Merck & Co., Inc.

Geoffrey Evans, Division of Vaccine Injury Compensation/HRSA

Lievano Fabio, Merck & Co., Inc.

Mark Feinberg, Merck & Co., Inc.

Gerald Ferguson, GlaxoSmithKline

Stephen Ford, Military Vaccine Agency

Vicent Frascatore, Merck & Co., Inc.

Sylvina Frutos, GlaxoSmithKline

Mary Gadek, Novartis

Stanley A. Gall, American College of Obstetricians & Gynecologists

Diana Gaskins, Division of Public Health, Georgia Immunization Program

Richard Gesser, Merck Research Laboratories

Christopher Gilbert, Merck & Co., Inc.

Ruth Gilmore, Georgia Immunization Program

Karen Goldenthal, Pharmanet Consulting

Michelle Goveia, Merck & Co., Inc.

John Gravenstein, Merck

Jesse Greene, SC Dept of Health and Environmental Control

Sylvester Gregg, Merck & Co., Inc.

Carolyn Griffing, Merck & Co., Inc.

Neal Halsey, Johns Hopkins University

Janice Hashimoto, Novartis

Richard Haupt, Merck & Co. Inc.

Alan Hinman, Task Force for Child Survival and Development

Phillip Hosbach, sanofi pasteur

Florence Houn, FDA

Wan-Ting Huang, CDC, Taiwan

Donnelle Humphrey-Franklin, Georgia DHR, Division of Public Health

Shirley Jankelevich, SC Dept of Health and Environmental Control

Uday Jodhpurkar, sanofi pasteur

David Johnson, sanofi pasteur

Eric Jones, sanofi pasteur

Nancy Kavanaugh, Medimmune, Inc.

Kevin Kelly, Merck Vaccine Division

Jason Kemner, GlaskoSmithKline

Glennie Kertes, Dwight D. Eisenhower Army Medical Center

David Kimberlin, AAP Committee on Infectious Diseases

Iftahar Koksal, Karadeniz Technical University, Turkey

Denise Kruzikas, GlaxoSmithKline

Barbara Kuter, Merck & Co., Inc.

Fred Lake, Cooney/Waters Group

Sarah Landry, GlaxoSmithKline

Scott Laster, Autism Parent

Jennifer Lastinger, Families Fighting Flu

Osman Leblibicioglu, Ondokuz Mayis University Medical School, Turkey

Grace Lee, Harvard Medical School

Marie-Michele Leger, American Academy of Physician Assistants

Jennifer Lichtner, Wyeth

Patrick Liedtka, Merck & Co., Inc.

Ding-Ping Liu, CDC, Taiwan

Brian Lotie, GlaxoSmithKline

Beverly Lybrand, Merck Vaccine Division

Andrew MacKnight, GlaxoSmithKline

Paul Madrazo, GlaxoSmithKline

Parthiv Mahadevia, Medimmune

Frank Malinoski, Medimmune

Leona Markson, Merck & Co., Inc.

Patrick Maroney, sanofi pasteur

Tara Martin, GlaxoSmithKline

Dean Mason, Wyeth

Marie Mazur, CSL Biotherapies

Jaime Micher, Asociacion Mexicana de Vacunologia

Patricia Montalvo, Las Vegas Palute Tribe Health and Human Services

Phillipe Monteyne, GlaxoSmithKline, Belgium

Kelly Moore, Tennessee Department of Health

Matthew Moore, CDC

Rebecca Morrison, SC DHEC Immunization Division

Jonathan Nelson, The Nelson Group

Timothy Obara, GlaxoSmithKline

Paul Offit, Children's Hospital of Philadelphia

Kevin O'Neill, Wyeth Vaccines

Walter Orenstein, Emory University

Shefali Parikh, Merck & Co., Inc.

Joanne Pattenier, GlaxoSmithKline, Belgium

Tamer Pehlivan, sanofi pasteur, Turkey

Georges Peter, Brown Medical School

Diane Peterson, Immunization Action Coalition

Stanley Plotkin, sanofi pasteur

Gregory Poland, Mayo Clinic and Foundation

Isabel Quasha, European Association for Cranio-Maxiollo-Facial Surgery

Jane Quinn, GlaxoSmithKline

James Ransom, NACCHO

Mobeen Rathore, University of Florida

Jill Ray, Georgia Chapter -- AAP

Greg Reed, CDC/NCIRD

Margaret Rennels, GlaxoSmithKline

Christina Richards, Johns Hopkins University Student Health Center

Lauren Riley, Infectious Diseases in Children, Slack Inc.

Julian Ritchey, sanofi pasteur

Maria Angela Roa, SciMed

Matthew Rousculp, Medimmune

Fred Ruben, sanofi pasteur

Alfred Saah, Merck & Co., Inc.

Thomas Saari, AAP Immunization Task Force

Patricia Sadler, Merck Research Laboratories

David Schechter, Merck & Co., Inc.

Laurie Schowalter, GlaxoSmithKline

Jason Schwartz, University of Pennsylvania

Anne Elizabeth Schuind, GlaxoSmithKline

Rosanna Selse, Johns Hopkins University

Tej Sha, WellCare

Tom Shin, Baxter BioSciences

Judith Shindman, sanofi pasteur, Canada

Jennifer Shu, Children's Medical Group, P.C.

Alan Sievert, American Academy of Pediatrics, GA Chapter

Heidi Spelete, Pediatric News

Silvija Staprans, Merck Vaccine Division

Gary Stein, Families Fighting Flu

Kurt Stembridge, GlaxoSmithKline

Mike Stobbe, Associated Press

Raymond Strikas, National Vaccine Program Office, HHS

Stacy Stuerke, Merck Vaccine Division

Florence Synn, Merck & Co., Inc.

Lonnie Thomas, Henry Schein Inc.

Rosemary Tierman, FDA/Division of Vaccines

John Trizzino, Medimmune

Theodore Tsai, Novartis

Mariam E. Tucker, Pediatric News

James Tursi, GlaxoSmithKline

Anastasios Tsirpouchtsidis, GlaxoSmithKline

Nevzat Ata Ualcin, Akdeniz University, Turkey

Sercan Ulusoy, Ege University, Turkey

Gaye Usluer, Eskisehir Osmangazi University, Turkey

Thomas Vernon

Peter Vigliarolo, Cooney/Waters

Michael Vinluan. CDC-INFO/Constella Group

Steven Vitale, GlaxoSmithKline

Robert Walker, Medimmune, Inc.

Joel Ward, Novartis

James Wassil, Merck & Co., Inc.

Barbara Watson, Philadelphia Department of Public Health

Rita Watson, Epilepsy Therapy Development Project

Deborah Wexler, Immunization Action Coalition

Patricia Whitley-Williams, UMDNJ Robert Wood Johnson Medical School

Matt Whitmann, GlaxoSmithKline

Mark Willmann, McCann Healthcare

Marcellette Wise, Wyeth Pharmaceuticals

Eileen Yamanda, California Department of Health Services

Laura Jean York, Wyeth Vaccines

Jennifer Zavolinsky, Every Child by Two

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Attachment Two: Acronyms

American Academy of Pediatrics (AAP)

Advisory Committee on Immunization Practices (ACIP)

Centers for Disease Control and Prevention (CDC)

Centers for Medicare and Medicaid Services (CMS)

Department of Health and Human Services (DHHS)

Food and Drug Administration (FDA)

Healthcare Utilization Project (HCUP)

Health Resources and Services Administration (HRSA)

Institute of Medicine (IOM)

Immunization Safety Office (ISO)

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

National Center for Immunization and Respiratory Diseases (NCIRD)

National Institutes of Health (NIH)

National Vaccine Advisory Committee (NVAC)

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

New Vaccine Surveillance Network (NVSN)

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

Vaccines for Children (VFC)

Vaccine Safety Datalink (VSD)