Final version February 21, 2006

Record of the Meeting of the Advisory Committee on Immunization
Practices (ACIP) on

February 21-22, 2006

Centers for Disease Control and Prevention

1600 Clifton Road, NE, Tom Harkin Global Communications Center (Building
19), Atlanta, Georgia

Table of Contents

Acronyms Used In This Report:

American Academy of Family Practitioners (AAFP)

American Academy of Pediatrics (AAP)

American College Health Association (ACHA)

Advisory Committee on Immunization Practices (ACIP)

American College of Obstetrics and Gynecology (ACOG)

Adverse Event (Seriours AE), ( AE (SAE))

Adenocarcinoma In-Situ (AIS)

American Medical Association (AMA)

American Society for Colposcopy (ASC)

American Society for Colposcopy and Cervical Pathology (ASCCP)

Atypical Squamous Cells Of Undetermined Significance (ASCUS)

Cost Benefit (Ratio), (CB®)

Behavioral Risk Factor Surveillance Survey (BRFSS)

Condom-Availability Programs (CAP)

Centers for Disease Control and Prevention (CDC)

Cost Effectiveness Ratio (CER)

Confidence Interval (CI)

Cervical Intraepithelial Neoplasia (CIN)

Dilation and Curettage (D&C )

Division of Cancer Prevention and Control (DCPC)

Department of Health and Human Services (DHHS)

Data Safety Monitoring Board (DSMB)

Division of STD Prevention (DSTD)

Diphtheria, Tetanus, Acellular Pertussis (vaccine) (DTaP)

Emergency Department (ED)

Enzyme-Linked Immunosorbent Assay (ELISA)

Food and Drug Administration (FDA )

Famiy Research Council (FRC)

Granulocyte Macrophage Colony (GMC)

Geometric Mean Titer (GMT)

GlaxoSmithKline (GSK)

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome
(HIV/AIDS)

Human Papilloma (Virus HPV)

High-Grade Squamous Intraepithelial Lesions (HSIL)

Herpes Zoster (HZ)

Intradermal (ID )

Infectious Disease Society of America ( IDSA)

Immune Globulin (IgA, class A, IgG, class G), ( Ig)

Intravenous Immune Globulin (IGIV)

Intramuscular (IM)

Investigational New Drug (IND)

Injected Polio Vaccine (IPV)

Live Attentuated Influenza Vaccine (LAIV)

Measles, Mumps, Rubella (Varicella) vaccine (MMR(V))

Meningococcal Polysaccharide Vaccine (MPSV)

National Association of County and City Health Officials (NACCHO)

National Center for Health Statistics (NCHS )

National Cancer Institute (NCI)

National Center for Infectious Diseases (NCID)

National Foundation of Infectious Diseases (NFID)

National Health and Nutritional Examination Survey (NHANES)

National Health Interview Survey (NHIS)

National Institutes of Health (NIH)

National Immunization Program (NIP)

National Survey of Family Growth (NSFG)

National Vaccine Program Office (NVPO)

National Vaccine Surveillance Network (NVSN)

Oral Polio Vaccine (OPV)

Papanicolau (cancer test) (PAP)

Post-Herpetic Neuralgia (PHN)

Purified Protein Derivative/Tuberculin Skin Test (PPD/TST)

Pentavalent Human Bovine Reassortant Rotavirus Vaccine (PRV)

Quality Adjusted Life Year (QALY)

Rotavirus Efficacy and Safety Trial (REST)

Request for Information (RFI)

Recurrent Respiratory Papillomatosis (RRP)

Rotavirus (RV )

Society for Adolescent Medicine (SAM)

Surveillance, Epidemiology and End Results (SEER)

Socioeconomic Status (SES)

Strategic National Stockpile (SNS)

Shingles Prevention Study (SPS)

Sexually Transmitted Disease (STD)

Vaccine Adverse Event Reporting System (VAERS)

Vaccine Efficacy (VE)

Vaccines for Children (Program) (VFC)

Virus-Like Particles (VLP)

Vaccine Safety Datalink (VSD)

Varicella Zoster Virus (VZV)

Varicella Zoster Immune Globulin (VZIG)

World Health Organization (WHO)

Acronyms Used In This Report

OCTOBER 26, 2005

OPENING COMMENTS

HUMAN PAPILLOMAVIRUS VACCINE

Background

The Biology of HPV

HPV Epidemiology in the U.S.

Cervical Cancer in the U.S.

GSK HPV Vaccine Clinical Trial Data

GARDASIL® Presentation

Cost Effectiveness of HPV Vaccination

Mathematical Modeling of HPV Vaccine

Behavioral Issues Related to HPV Vaccination

Options for ACIP Recommendation on HPV Vaccine

PUBLIC COMMENT

ROTAVIRUS VACCINE

Data Review, Rotavirus Efficacy and Safety Trial (REST)

Rotavirus Vaccine Working Group Draft Proposed Recommendations

Vote

VFC Resolution

ACIP GENERAL RECOMMENDATIONS ON IMMUNIZATION

Revisions to the General Recommendations

New Revisions to the General Recommendations since October 2005

Public Comment

FEBRUARY 22, 2006

CDC DIRECTOR'S COMMENTS

OLD BUSINESS

Resolution to Add Rotavirus Vaccine to the VFC

Vote

Changes to the ACIP General Recommendation

Vote

VARICELLA ZOSTER IMMUNE GLOBULIN

VZIG Update: Availability of a New Product

INFLUENZA VACCINE

Introduction

Review of 2005 Influenza Vaccine Summit Meeting.

Presentation by National Foundation for Infectious Diseases

Influenza Surveillance Data Update

Key Issues/Changes Proposed for the 2006-07 Influenza Recommendations

Vote

Recommended influenza vaccination for children aged 24-59 months

Vote

Vote

VFC Changes Relevant To Influenza Vaccine

Vote

Update on HHS Pandemic Influenza Planning

NIH/NIAID H5N1 Update

TETANUS-, DIPHTHERIA TOXOID, ACELLULAR PERTUSSIS VACCINES

Report from the Pertussis Working Group

Manufacturer Updates

Tdap Use Among Adults Aged \>65 Years

Vote

Tdap Use Among Healthcare Workers

Cost-Benefit Analysis of Tdap Vaccination of Health-Care Workers

Proposed Tdap Recommendations

Vote

HERPES ZOSTER (SHINGLES) VACCINE

Storage/Handling of Herpes Zoster Vaccine

Survey of Internists/Family Care Practitioners About Herpes Zoster
Vaccine

Shingles Prevention Trial, Zostavax®

Public Comment.

ACIP EVIDENCE BASED RECOMMENDATION CLASSIFICATIONS

Closing comments.

Appendix: Attendance

**CENTERS FOR DISEASE CONTROL AND PREVENTION**

**NATIONAL IMMUNIZATION PROGRAM**

**ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES**

**MINUTES OF THE MEETING**

**FEBRUARY 21-22, 2006**

**OCTOBER 26, 2005**

A meeting of the Advisory Committee on Immunization Practices (ACIP) was
convened by the Centers for Disease Control and Prevention's (CDC)
National Immunization Program (NIP) at the CDC Global Communications
Center in Atlanta, Georgia, on February 21-22, 2006. This report is
organized according to the meeting agenda, which was posted on CDC's
ACIP website and distributed at the meeting. ACIP Chairman Dr. Jonathan
Abramson convened the meeting at 8:02 a.m., welcoming all in attendance
(see Attachment #1).

**OPENING COMMENTS**

ACIP Executive Secretary Dr. Larry Pickering made several announcements:

-   He welcomed the new NIP Director, Dr. Anne Schuchat; Dr. Robert
    Davis, director of the CDC Immunization Safety Office (ISO); and Dr.
    Jean Smith, Assistant to the NIP Director for Immunization Policy.

-   New liaisons present were Dr. Jeffrey Duchin, for the NACCHO.

-   Dr. Renee Jenkins attended for Dr. Patricia Whitley-Williams (NMA),
    as did Dr. Mark Whitaker for Dr. Andrea Gelzer (AAHP). Dr. Charles
    Helms (NVAC) was absent.

-   The ACIP home page is
    [www.cdc.gov/nip/acip](http://www.cdc.gov/nip/acip) and the email
    address is acip@cdc.gov.

-   The remaining 2006 ACIP meeting dates are June 29-30 and October
    25-26.

-   ACIP Protocol: A quorum of ACIP members must be maintained to
    conduct committee business. In the absence of a quorum (eight
    members) of members qualified to vote, the ACIP charter allows the
    Executive Secretary to temporarily designate ex officio members as
    voting members. If voting, the ex-officio members are asked to
    disclose any potential conflicts of interest. ACIP members with
    potential conflicts of interest are asked to disclose all
    vaccine-related work and financial interests, and to refrain from
    any discussion or vote that is related to such matters. When needed,
    however, limited waivers of such conflicts of interest can be
    granted to enable the members to provide their expertise to the
    Committee. Waivers may be issued, for example, to members who also
    conduct clinical vaccine trials, or who serve on a Data Safety
    Monitoring Board (DSMB). Those members may provide information to
    the committee and discuss other vaccines produced by the same
    company, but they may not participate in discussion on the vaccine
    involving their conflict, nor in any related votes.

-   Meeting time is reserved for public comment at scheduled intervals,
    but may also occur during open discussion if time permits and the
    Chair recognizes a speaker.

-   Slide presentations from this meeting were posted on the ACIP
    website after the meeting.

The members and liaisons then introduced themselves (see Attachment #1).
Those reporting potential conflicts of interest were Mr. Beck (awaiting
a decision from the Office of General Counsel about stock), Dr. Gilsdorf
(uncompensated, independent safety monitor for an NIH-sponsored vaccine
trial, but not compensated); Dr. Harry Hull (discussing potential
projects with MedImmune); Dr. Greg Poland (chairs a Merck DMSB, serves
on the DVC scientific advisory board and has conducted clinical trials
for Chiron, Merck, and Vaxgen); and Dr. John Treanor (conducting
influenza vaccine clinical trials for Merck, GlaxoSmithKline (ID
Biomedical); Protein Sciences Corporation, and conducting laboratory
studies for AlphaVax).

**HUMAN PAPILLOMAVIRUS VACCINE**

***Background***

Dr. Janet Gilsdorf, HPV Working Group Chair

Overview: Summary of HPV vaccine Working Group activities

-   The HPV vaccine Working Group was formed in February 2004; members
    include representatives from ACIP, FDA, NIH, NIP, DSTD, DCPC, NCID
    and Consultants/liaisons from AAP, AAFP, ACOG, SAM, IDSA, ACHA.
    There have been presentations from industry, academia and at least
    monthly conference calls to review trial data.

-   Two HPV vaccines are in development. Both vaccines have a three-dose
    schedule; GSK's bivalent targets females and Merck's quadrivalent
    targets both genders. Both companies outlined product development
    plans and initial data for ACIP in February 2005 and Merck's
    efficacy data were presented that October.

-   On this day, presentations addressed the background on HPV biology,
    epidemiology, and cervical cancer in the U.S.; preliminary efficacy,
    immunogenicity, and safety data for the GSK bivalent HPV vaccine;
    efficacy, immunogenicity, and safety data for the Merck quadrivalent
    HPV vaccine; modeling data on cost effectiveness/impact of HPV
    vaccine; HPV-related sexual behavior; and considerations regarding
    recommendations for use of the Merck HPV vaccine.

    ***The Biology of HPV***

Presenter: Dr. Doug Lowy, NCI

> Overview: HPV biology. Disclosure: Dr. Lowy is an inventor of the VLP
> vaccine technology that is patented by NIH and licensed to Merck and
> GlaxoSmithKline.

Cervical cancer is the second most common cancer of women worldwide. It
represents about 10% of all cancers of women with \~70% of these cancers
being caused by HPV-16 and HPV-18. HPV16 also causes other mucosal
epithelial cancers. The HPV vaccines target HPV-16 and HPV-18. The Merck
vaccine also targets HPV-6 and HPV-11, which cause most external genital
warts. Nongenital, common or flat warts are also caused by HPV, but by
types other than those in the vaccines.

The capsid of the HPV virion is composed of 360 copies of the L1 the
major structural protein (arranged as 72 pentamers), and a smaller
number of copies of L2, the minor structural protein. . L1 contains the
immunodominant neutralization epitopes, which are conformation-dependent
and predominantly type-specific. When L1 is expressed in cells, it is
sufficient to form virus-like particles (VLPs) whose structure resembles
authentic virion capsids. The L1 VLPs contain the neutralization
epitopes, so that they induce high titers of neutralizing antibodies.
When L1 and L2 are co-expressed in cells, they associate with each other
and form L1/L2 VLPs. In studies with animal papillomaviruses, systemic
immunization with L1 VLPs was highly protective against high-dose
experimental viral challenge, and L1/L2 VLPs did not confer additional
protection. Therefore, vaccine development has focused on L1 VLPs. The
animal studies also showed that neutralizing antibodies are probably the
main protective activity induced by the VLPs, since passive transfer of
immune IgG is protective. The vaccine was active prophylactically, but
not therapeutically against established lesions. Heterologous
neutralizing antibodies were not protective, implying that the
protective factor is type-specific. The neutralizing antibodies can work
by interfering with the binding of the virus to the cell, with its
cellular uptake upon binding, or with its uncoating inside the cell.

HPVs infect stratified squamous (i.e., multilayered) epithelia. To
establish a persistent infection, the virus must infect cells in the
basal epithelial layer, which contains the epithelial stem cells and is
the main source of dividing cells in this tissue. Access of the virus to
the basal cells is believed to require microtrauma to the epithelium.
Microtrauma in the genital area can lead to the acquisition of HPV
infection through sexual intercourse with an infected partner. Chronic
infection is established because the viral genome resides in the basal
stem cells or in long-lived basal cells.

Several factors may contribute to the ability of the neutralizing
antibodies induced by the vaccine to protect against infection of the
female genital tract. One is that IgG is the main immunoglobulin in the
female genital tract, and neutralizing IgG antibodies, which are the
main class induced by systemic immunization, are transudated into the
female genital tract. Another is that the epithelial microtrauma that in
the absence of neutralizing antibodies predisposes to infection may
provide access to the systemic antibodies, thereby increasing the local
concentration of neutralizing antibodies.

The L1 VLP vaccines are unlikely to be directly therapeutic,
particularly for the intermediate and high-grade dysplasias, as these
lesions express little or no L1 protein. The vaccines might
theoretically have some therapeutic activity for low-grade lesions, as
they do express L1 protein. However, most of the L1 protein is in the
upper layers of the epithelium, and resolution of the lesion would
require that the L1 protein in the lesion produce a sufficiently robust
reaction to destroy the basal cells that harbor the viral genome. It is
more likely that the VLP vaccine may reduce HPV spread from an infected
site to a previously uninfected site by neutralizing the virus that
comes from a lesion. In summary, the L1 virion immunodominant epitopes
are conformation-dependent. Preclinical studies indicate that
vaccination with L1 VLPs induce neutralizing antibodies that are
predominantly type-specific. Systemic immunization could deliver these
antibodies to sites of microtrauma from sexual intercourse. In addition
to preventing new infection, an L1 VLP vaccine might reduce HPV spread,
but it is not likely to treat established lesions, particularly
moderate- or high-grade dysplasias..

***HPV Epidemiology in the U.S.***

Presenter: Dr. Eileen Dunne, DSTDP

> Overview: HPV infection and disease burden of HPV-associated
> conditions in the U.S., principally among women; sexual transmission;
> laboratory diagnostic methods, treatment; issues of immunity and
> serology.

The prevalence of HPV infection is high in both males and females. Of
the \>100 HPV types, approximately 60 types are cutaneous and cause the
common skin wart. The 40 mucosal types are divided into high-risk types
and low-risk types. High-risk HPV types are epidemiologically associated
with cervical and other anogenital cancers. Of those, two of the most
important are HPV-16 and HPV-18. The most common of the low-risk HPV
types are HPV-6 and HPV-11. Multiple HPV types are often detected, but
HPV-16 is the most common type, with a 10% cumulative incidence at two
years after first sexual intercourse. HPV persistence is associated with
increased risk of cervical cancer precursors and cervical cancer.
Information on HPV infection among men is limited, but natural history
studies are ongoing. There is limited utility for HPV serology as a
marker of cumulative incidence because serological tests will
underestimate past or current HPV infection.

The HPV types associated with cervical cancer around the world were
analyzed by Clifford et al (*Br J Cancer*, 2003) in a meta-analysis of
studies evaluating cervical cancer biopsy samples for HPV types. Types
16 and 18 were consistently associated with \>70% of cervical cancers
worldwide. The conditions associated with HPV-16, -18, -6, and -11 were
listed, indicating the potential benefit of a quadrivalent HPV vaccine.
Other than cervical cancer, HPV-16 and -18 also cause a high proportion
(80%) of high- and low-grade cervical abnormalities; anal and anogenital
cancers, and \~10% of head and neck cancers. The low-risk Types 6 and 11
cause 90% of genital warts and recurrent respiratory papillomatosis, as
well as low -grade cervical abnormalities.

Among HPV-6 and -11 associated conditions are genital warts and
recurrent respiratory papillomatosis (RRP). The peak prevalence of
genital warts appears to be at ages 20-29 years in both men and women;
one study demonstrated the incidence rate at 157/100,000 persons. These
warts recur in 30% of cases and cause multiple treatment visits. RRP is
a condition in which warts grow in the respiratory tract, a rare but
debilitating and recurrent disease that can require multiple surgeries.
It is most common in juveniles and is most likely maternally
transmitted. Estimated prevalence of juvenile-onset RRP is 1-4/ 00,000
children aged \<18 years, and incidence is 0.1-2.1/100,000 children. A
voluntary RRP registry indicates a median of 13 lifetime surgeries, with
a range of 2-179 surgeries.

HPV acquisition occurs soon after sexual initiation, with most
infections clearing quickly, but some persisting. The lifetime
cumulative incidence is high, models have demonstrated \>80% of persons
have had infection with HPV by age 50. Persistent infection is
associated with high grade cervical intraepithelial neoplasias (CIN)
which can lead to cervical cancer. Screening with the routine Pap tests
can usually detect these early for treatment.

Transmission of HPV occurs primarily by sexual contact, usually sexual
intercourse. However, other types of sexual contact can transmit HPV,
but transmission occurs much less frequently. Transmission is determined
by per partner transmission probability, infectiousness, and average
number of partnerships formed per unit time. There is no epidemiologic
data on HPV transmission probability per sex-act, or per partnership,
however models estimate that 0.4 as a median probability of per-sex act
transmission, and 0.6 as a probability of transmission per-partnership,
in another. This would mean that transmission would likely occur by
three sex acts. Sex, age, infection site, immune status, and HPV type
may also contribute to risk of transmission.

With regard to HPV laboratory methods, there is no culture for HPV,
detection of DNA is used to measure infection. HPV DNA detection occurs
by PCR or, in a cervical cancer screening and management clinical
setting, by a hybridization assay (the Digene Hybrid Capture II). This
HCII test detects 13 high-risk HPV types. Other tests available include
HPV serology, which is an ELISA type-specific antibody serology (IgG or
IgA) test to L1 VLPs. This test can test for serum or mucosal
antibodies, and there is poor standardization of methods.

There are certain challenges to describing the epidemiology of HPV
infection in the U.S. There is no culture for HPV infection, detection
of DNA is used to measure infection. Presence of HPV DNA does not
necessarily indicate infectious virus. National incidence and
surveillance data are very limited, as there is not routine testing for
HPV infection, nor is there reporting of HPV infection or HPV-associated
conditions. And, HPV infection or HPV-associated conditions are not
always associated with antibody detection.

> U.S. national HPV prevalence has been estimated at 20 million people
> or 15% of Americans aged 15-49 years. Estimated incidence is 6.2
> million infections annually (\>50% of sexually active men and women
> over their lifetime).
>
> The 2002 National Survey of Family Growth and 2003 Youth Risk
> Behavioral Survey indicate that \~7% of young persons have had sex
> before age 13 years, 25% by age 15 years, and 48% by 17 years. An
> estimated 14% of females and 18% of males aged 15-19 years have had ≥2
> sex partners in the last 12 months.
>
> A review of HPV prevalence studies (Revzina NV. *Int J STD/*AIDS,
> 2005) showed high HPV DNA prevalence among U.S. women in all clinic
> settings (e.g., STD, family planning clinics). Not surprisingly, the
> highest prevalence was in STD clinics (49-90% of females had HPV
> infection).
>
> A CDC cross-sectional analysis of HPV infection among women having a
> Pap test in six U.S. cities (N=5500, aged 14-65 years) from 2003 to
> 2004, found the highest prevalence (40%) of high-risk HPV infection
> among 14-19 year-olds. Prevalence of HPV infection decreased with
> older age. HPV prevalence by race/ethnicity was similar; somewhat
> lower among Asian women, but not significantly when age-adjusted.

-   The prevalence of HPV of any type was 26.9% among college women aged
    18-25 years (N=3262), as determined by less sensitive urine methods
    (Manhart L, *STD*, in press). Prevalence of HPV ranged from 0.2-5.8%
    among types 6, 11, 16 and 18, with Type 16 being the most common.
    The same data analyzed by number of sex partners found 14% HPV
    prevalence in these women, even with one sex partner. This rose with
    increasing numbers of lifetime sex partners.

-   Winer et al (*Am J Epidemiol,*2003:157) followed young college women
    after sexual initiation, and found HPV was acquired soon after first
    sexual intercourse. Two years after first sexual intercourse,
    cumulative incidence of any HPV infection was 40%, and \>50% four
    years later. At 2 years, type-specific cumulative incidence was
    0.9-10.4% percent,; the highest acquisition was for HPV-16.

*Persistent HPV* is often defined as infection detected at more than one
visit, usually at four to six months apart. That is an important
predictor for high-grade cervical cancer precursors and invasive
cervical cancer (10% by Schlecth et at, *JAMA*, 2001; and 14.1% by
Moscicki et al, *J Pediatr*, 1998). Other risk factors have included HPV
Type 16; immune status; smoking; multiple HPV-type infections; older
age; and certain STDs, including chlamydia and herpes. Immune response
to infection is important to clear infection, but the immune response to
HPV remains unclear.

Data on type-specific HPV immunity are few, but some studies demonstrate
few women later re-acquire the same type of infection if that type has
been cleared. This suggests short-term, type-specific immunity. There
are no longitudinal cohort studies to assess immunity over a lifetime.
Natural history studies have found no cross-protection between HPV
types.

*HPV infection in men* has been less studied, but the few existing
studies demonstrate equal HPV prevalence to that of females, depending
on the site and sample collected. Several ongoing longitudinal studies
are assessing HPV clearance and persistence, and the development of
HPV-associated conditions among men. Weaver (2004) estimated prevalence
at 35% among 318 university students aged 18-25, and Baldwin (2003)
estimated 28.2% in 443 STD clinic patients aged 18-70. Men's HPV risk
factors include sexual behavior, immune status, and in some, lack of
circumcision. Some studies identified STD history or inconsistent condom
use associated with HPV infection as well. HPV Types 16 and 18 are
associated with anal, penile, and head and neck cancers among men, and
HPV-6 and -11 are associated with anogenital warts and RRP among men.

As described earlier, HPV serology is an ELISA-based detection of
antibodies to VLPs. The tests are type-specific, but since many infected
persons do not develop antibodies, ELISA likely underestimates the true
burden of infection and disease. HPV-16 seropositivity in the U.S.,
estimated from NHANES data, was low at 2.4% for those aged 6-11 years
old, and 13% for those 12-59 years.

***Cervical Cancer in the U.S.***

Presenter: Dr. Herschel Lawson, Division of Cancer Prevention and
Control

> Overview: Review of cervical cancer and other HPV-related cancers in
> the U.S.; surveillance, disease burden, screening, diagnosis: costs:
> cervical cancer, cervical cancer precursors, other HPV-related cancers

Worldwide, breast cancer is the most common cancer among women. Cervical
cancer incidence is much lower in industrialized countries than those
less developed, where it is the second most common cancer in women. The
higher burden of disease is very likely due to the absence of screening
programs in a large part of the developing world.

Surveillance data on U.S. cervical cancer incidence are collected and
housed in the National Program for Cancer Registries (NPCR),
administered by CDC/DCPC, and the NIH/NCI Surveillance Epidemiology and
End Results program (SEER). The NCHS, in CDC, houses cervical cancer
mortality data.

*Cancer incidence* in 2002 was 12,000 cases, of which 80% were squamous
cancers and 20% adenocarcinomas (glandular cancers). There were \~4000
cervical cancer deaths. The American Cancer Society estimate for 2005 is
10,000 cases and in 2002, there were 9.2 cervical cancer cases per
100,000 women, similar in proportion to cancers of the bladder,
pancreas, kidney, leukemias and renal disease. That rate was the product
of a dramatic decline from the late 1950s, when the Pap tests became
common. However, there are still racial disparities in the incidence and
mortality of cervical cancer, with black women still having higher rates
than white women. The incidence and mortality rates also rise with age,
peaking in the late 30s to early 40s, and then again in the mid- to late
60s. Death rates increase with age in all groups.

Interestingly, cervical cancer incidence and death is geographically
skewed, highest along the Appalachian mountains, in concentrated pockets
of the Ohio and the Mississippi River valleys, along the Texas-Mexico
border, and scattered throughout the country.

The greatest risk factor (60%) for cervical cancer in the U.S. is not
being screened or being screened at intervals that are greater than 5
years. Of the 40% of cancers detected in women screened, false negative
tests, loss to follow-up after positive cytology, and mismanagement made
up 25-40% of cases and rapidly progressive or hard to detect, uncommon
cancers such as adenocarcinomas made up 14%-22% of cases. The
conventional Pap test has been largely replaced in the last ten years by
liquid-based cytology. Surveys suggest that 85% of cytology testing is
currently performed using the liquid-based method. Slides of the two
methods were shown. The conventional cytology test is known to be less
sensitive than liquid-based cytology, but more specific than the
liquid-based cytology. As a result, more false-positive results have
occurred requiring additional testing for more women ultimately not
found to have cervical cancer or pre-cancer.

The NCI reporting system for abnormal Pap results was outlined: atypical
squamous cells of undetermined significance (ASC-US), atypical squamous
cells, cannot rule out high-grade disease (ASC-H), low-grade (LSIL) and
high-grade squamous intraepithelial lesions (HSIL), and squamous cell
cancer. For glandular cells, atypical glandular cells (AGC) are
reported, as are adenocarcinoma in-situ (AIS); and adenocarcinoma.

Three organizations have issued cervical cancer screening
recommendations, ACOG, the USPSTF, and the ACS. They agree that
screening should begin at about age 21, or within three years of
beginning sexual activity. The recommended intervals for screening vary
from one to three years.

BRFSS and NHIS data from 2000 were charted to show the prevalence of
cervical cancer screening cytology done in the U.S. Overall, 82% of
women are screened, but more women are screened who have insurance than
those without it, and fewer foreign-born than native-born women are
screened. (Swan J et al, *Cancer* 2003;97:1528-40). There are also
racial/ethnic disparities, with Asian women least likely (at 71%) to be
screened.

*HPV testing.* The FDA has approved only one HPV test, the
previously-mentioned Hybrid Capture II. This is a hybridization assay
that amplifies signals with long synthetic RNA probes that are sensitive
to the 13 high-risk HPV types. It is easy to perform in the clinical
laboratory and can be automated. The FDA approved this for triage (e.g.,
to determine if an ASC-US Pap test is associated with a high-risk HPV
type) and for primary screening to complement the Pap test in women aged
≥30 years. In the latter group, if both tests are negative, a three-year
screening interval should be used. ACOG, ASC, and the ASCCP recommend
using the HPV DNA test.

The number of Pap tests done annually in the U.S. is not known, but the
NCI estimates that a base of \~50-60 million Paps per would produce \~2
million ASC-US results; 1 million LSILs (an acute HPV infection); \~
300,000 HSILs, and \~15,000 cancer reports (A. Hildesheim, NCI). Not all
of the cancer Pap reports turn out tol be invasive cancer. Normal follow
up of abnormal cytology may include a repeat test, or HPV DNA, vaginal
and cervical inspection, colposcopy with directed biopsy, endocervical
curettage, and manual pelvic examination.

*Cost.* CDC modeled HPV's direct costs at \~\$4 billion dollars a year,
almost all of which (90%) stems from abnormal cervical cytology and
treatment of cervical neoplasia. Cervical cancer costs accounted for 4%
of the total, and management of anogenital warts accounted for the
remaining 6%. Oncogenic HPV is also associated with anal, vulvar, and
vaginal cancer, as well as cancer of the penis. About 15-20% of
oropharyngeal cancer is attributable to HPV types.

***GSK HPV Vaccine Clinical Trial Data***

Presenter: Dr. Gary Dubin, GSK

Overview: New data from the GSK HPV vaccine-development program.

GSK's vaccine is designed to prevent cervical cancer in women,
particularly from the most common types, HPV16- and -18, which cause
70%  of cervical cancers. The vaccine uses an adjuvant to enhance immune
responses to the VLPs. Long-lasting protection is a goal, as the vaccine
indication will go down to age ten years to prevent invasive cervical
cancer and the precursors associated with oncogenic HPV infection.

The GSK vaccine's VLPs are made from the recombinant L1 proteins of
HPV-16 and-18. These self-assemble to VLPs that resemble intact virions
and prompt immune responses such as the generation of neutralizing
antibody. The vaccine has 20 μg of each VLP of HPV-16 and-18, plus two
adjuvant components: aluminum hydroxide and alum plus monophosphoryl
lipid A (ASO4). The latter boosts the immune response to VLPs.

Phase I and II studies assessed vaccine safety, immunogenicity, dose
ranging of the VLP components, and different adjuvant formulations. In
phase IIa studies, the adjuvant vaccine was compared to that with only
aluminum hydroxide salts and GMT antibody titers were charted for HPV-16
and-18. The women received three shots at 0, 1, and 6 months and were
followed (to now) for up to 48 months. Peak responses of the adjuvant
vaccine exceeded the other, and approximately two-fold higher GMT
functional or neutralizing antibody has persisted. That was one reason
this formulation was carried forward for testing.

Two phase IIb studies were outlined. HPV-001 was an efficacy,
immunogenicity and safety study in the U.S., Canada and Brazil. This
followed 1113 subjects over two years for virologic and cytologic end
points, and biopsy-confirmed CIN lesions. HPV-007 extended -001 for
another two years.

*New data*. To date, the AS04 adjuvant has been assessed in vaccines
under development other than HPV in 40 completed and 3 ongoing studies
involving \>16,000 subjects and 43,000 vaccine doses. The AS04 vaccines
have been generally safe and well tolerated. The two largest programs
are, 1) of a genital herpes simplex virus (gD ASO4) vaccine now in large
Phase III trials, including a collaborative NIH efficacy trial; and 2)
the development program for Fendrix®, which is targeted to hemodialysis
patients who respond poorly to the standard hepatitis B vaccine. It was
approved by the E.U. in early 2005.

*HPV-001 efficacy study.* This double-blind, randomized controlled trial
involved 1113 women assigned to either the HPV vaccine or alum control,
followed for 18-27 months from enrollment. The endpoints were HPV-16
and-18 infections and associated cytologic abnormalities and cervical
lesions. The vaccine was shown to be safe and well tolerated, inducing
antibody responses at titers higher than natural infection in almost all
subjects. Efficacy was high, with 100% protection against persistent (6
months) HPV-16 or -18 infection, and the same for biopsy-confirmed CIN
lesions with demonstrated HPV-16 or-18 in the DNA; protection from
abnormal HPV-16/18 Pap smears was 93%. There was also preliminary
evidence found of protection against other oncogenic HPV types (31 and
45), which are phylogenetically related to HPV-16 or -18.

*HPV-007* was a long-term, blinded follow-up to -001, which evaluated
the same end points as the initial trial over another 36 months.
Preliminary interim analysis has been done of the first 12 months of
follow-up, providing a total of 48 months with the parent studies. The
extension involved 776 subjects randomized to the intent-to-treat
cohort. Efficacy was assessed against incident infection for HPV-16
or-18; persistent infection (6- and 12-months), abnormal cytologies
associated with HPV-16 and-18, and biopsy-confirmed CIN lesions. The
demographic characteristics of the enrolled subjects were outlined.

*Immunogenicity.* Study -001 revealed a peak antibody response to HPV-16
and -18 at month seven. By about month 18, antibody titer declines to a
plateau at about one log lower than the peak, but still tenfold higher
than that from natural infection with either HPV-16 or -18. Over 98% of
subjects maintained seropositivity for HPV-16 or -18, even to month 53.

*Efficacy.* VE was 100% over two years of follow-up against persistent
infection and CIN lesions. VE was also 100% during the extension phase
to year four against 12 month persistent infection and CIN lesions,
showing good duration of protection. In addition, the vaccine was most
efficacious against the end points with the highest predictive values
for cervical cancer (i.e., 12 month persistent infection or a CIN
lesion). No subjects in the vaccine group developed either CIN 1 or CIN
2 or worse lesions associated with HPV-16 or -18, although some of the
controls did. Efficacy also was \~96% for ASC-US or worse cytologies
associated with HPV-16 or-18.

Vaccine efficacy was also maintained for the four years of follow-up
against virologic end points (incident infection and 6- and 12-month
persistent infection, with efficacy levels of 94.7%, 96% and 100%,
respectively). Study -007 looked for evidence of waning protection,
which might be signaled by increasing numbers of endpoints in vaccine
recipients. Instead, during the HPV-007 study, VE against incident
infection with HPV-16 or -18 remained high, at 95.8% and 100%,
respectively ─ in fact, higher than those seen in the first two years of
follow-up.

*Conclusions.* Almost 100% seropositivity was maintained out to
53 months after study enrollment. Protection did not wane through a mean
of 48 months for virologic, cytologic or histopathologic end points
(including incident and persistent infections). There were no
vaccine-related serious adverse events in any portion of the studies.

*Phase III* studies are underway. One is GSK's multicenter,
double-blind, randomized controlled trial (HPV-008) in 14 countries
using hepatitis A vaccine as the control, and involving \>18,000 women
aged 15-25 years. NCI is doing a second Phase III study (HPV-009)
similar to GSK's, but in a population-based efficacy study in Costa Rica
with six study centers and 7500 women aged 18-25 years. Both studies are
assessing VE against CIN 2-plus lesions associated with HPV-16 and -18
as the primary end point, and both have independent DSMBs.

Additional "age-bridging" trials are being done to extend down to age 10
and past age 25. This is hoped to provide protection before sexual
debut, as well as protect women aged \>25 who remain at risk of new HPV
infections.

-   HPV-012, which targets preteen and adolescent girls, is an
    immunological bridging study to compare the immune responses of
    girls aged 10-14 to those aged 15-25 years, as well as safety and
    reactogenicity. *Results*: The safety profile was similar between
    the 10-14 year-olds and the 15-25 year olds, but the 10-14
    year-olds' GMTs were more than two-fold higher than those of the
    15-25 year-olds. There were no serious adverse events related to
    vaccination and the reactogenicity profile was the same for all the
    groups.

-   Recently completed, HPV-013 studied safety and immunogenicity in
    10-14-year-old girls. Those data should be presented in the near
    future.

-   HPV-014 is an immunological bridging study of women aged 25 years,
    comparing their immune responses to those of the 15-25 year-old
    efficacy cohort.

A timeline of the Phase III studies was shown from 2005 to 2009,
involving \>30,000 subjects. The efficacy studies HPV-008 and HPV-009
will go at least through 2009, as will the long-term follow up of the
adolescent safety study to examine the kinetics of antibody responses,
especially in the 10- to 14-year age range over time. Another long-term
follow-up to 2007 will be done to compare immune responses of women aged
\>25 to those aged 15-25 years.

Data will be released over the next few months for HPV-013 (adolescent
safety data), HPV-014 (immunobridging 15-25 years and 26-55 years), more
data from HPV-007 (overall efficacy against cytological/histological
endpoints regardless of HPV DNA lesion status), and health economic
modeling data.

GSK plans to apply for U.S. licensure by year's end, and also will file
for European licensure this year. Post-licensure work will study
efficacy in \>5000 women aged \>25 years, assessing persistent infection
and CIN over at least three years; the vaccine's co-administration with
routine adolescent vaccines; and safety and immunogenicity in
HIV-positive women. Phase IV studies being planned include long-term
follow-up (10-15 years) of cancer and pre-cancer among \>5,000 Phase III
subjects in Finland. Other Phase IV studies should begin in 2007.

***GARDASIL® Presentation***

Presenter: Dr. Eliav Barr, Merck & Co., Inc.

> Overview: GARDASIL® description; GARDASIL® clinical trials design,
> focusing on the choice of efficacy endpoints and target populations;
> clinical trials results.

The primary analysis of Merck's Phase III trials in adolescents and
young women have been completed. The vaccine targets HPV types 16, -18,
-6 and -11. HPV-6 and -11 are responsible for \>90% of genital warts and
recurrent respiratory papillomatosis (RRP) lesions in both boys/men and
girls/women. These types also cause 10% to 15% of CIN 1 lesions. Because
HPV-6 and -11 related CIN 1 lesions are morphologically
indistinguishable from the HPV-16 and-18 CIN 1 lesions, they therefore
are treated as precancerous, imposing an additional economic and
psychologic burden.

Studies of GARDASIL® have been conducted in women and in men. While the
clinical sequelae of HPV infection are better understood in women vs.
men, HPV infection imposes a heavy burden on men (cancer, RRP, genital
warts). Men also represent the primary mode of HPV transmission to
women.    

GARDASIL® is a quadrivalent, virus like particle (VLP) vaccine. It is
not a live virus. It has four VLP types manufactured in yeast with
Merck's proprietary aluminum adjuvant. It is given in three doses at day
1, month 2 and month 6. The vaccine must be stored at 2oC to 3oC. FDA
has granted priority review for Merck's December 2005 application for
licensure and the action date is June 2006. Prophylactic administration
of the vaccine has been shown to prevent HPV-16 and -18 related
cervical, vulvar, and vaginal cancer, as well as HPV-16 and-18-related
CIN 2, CIN 3, and AIS, and VIN 2/3 and VaIN 2/3, the precursor lesions
to vulvar and vaginal cancer. Prophylactic efficacy was demonstrated for
all four HPV types for infection, low-grade dysplastic lesions, genital
warts, and low-grade flat warts, for 9-15-year-old boys and girls and
16-26-year-old adolescent and young adult women. Future applications
will provide data to extend the age indication to young adult men and
women aged \>26 years.

*Study design.* The trials' primary end points were prophylactic
efficacy for HPV-related cervical, vulvar, and vaginal cancers and their
precursors, genital warts, and persistent infection. Additional end
points were the vaccine's impact on HPV disease burden in women and on
the course of existing HPV vaccine-type infection.

*End points.* Clinical trials for a vaccine to prevent cervical cancer
are not possible because HPV infection takes \~20 years to become
cancer, and due to the requirement to provide cervical cancer screening
women during the trial thereby treating subjects before they develop the
cancer). So, intermediate end points were selected: initial HPV
infection (which normally clears), HPV-related CIN 1 (important from a
health-economics perspective), and most important, CIN 2/3 and
adenocarcinoma in situ, the intermediate and obligate precursors to
cervical cancer and the targets of screening programs. Preventing CIN2/3
and AIS prevents cervical cancer. Demonstration of prophylactic with
respect to CIN2/3 and AIS cause by vaccine HPV types was approved by the
FDA advisory committee as the basis for U.S. licensure.

HPV-related vulvar and vaginal cancers have the same natural history.
Vulvar cancer incidence is rising among young American women. HPV,
primarily HPV-16 and-18, being involved in \~70% of vulvar and vaginal
cancer biopsies. Their immediate precursors are the VIN 2/3 and VaIN 2/3
lesions, which have a high rate of progression to cancer.

Immunogenicity. It will be particularly important to protect 9-15
year-old children using prophylactic HPV vaccines, as such subjects are
sexually-naive and HPV infection occurs shortly after sexual debut. The
efficacy of GARDASIL(R) in 16- to 26-year-olds was bridged to
pre-adolescents using an immunogenicity bridging program.  Long-term
efficacy data are being generated to find immune correlates and to
define the duration of immune response to GARDASIL®, in order to address
HPV's lifelong risk for women. Also pursued were data on
co-administration with other common adolescent vaccines. Vaccine safety
was evaluated in all the populations indicated, and a pregnancy outcomes
follow-up program in clinical trials of GARDASIL vaccines was
established. Understanding the vaccine-pregnancy interaction is
important, since the vaccine will be administered for women of
childbearing age.

HPV infection risk is closely tied to sexual debut. The proportion
of 10- to 14-year-old subjects with evidence of HPV disease is low.
However, after sexual debut, the proportion of the female population
with evidence of HPV disease rises dramatically. The peak incidence of
new HPV disease in women occurs between ages 16 and 25 in both men and
women. The clinical efficacy trials focused on 16-26 year-olds, the
period of highest risk to acquire HPV, as well as the period of most
cytologic abnormalities and rates of CIN. This group would benefit
dramatically from a prophylactic HPV vaccine. Immunogenicity bridging
studies were done to demonstrate an immune response in the younger age
group. Studies are being done to evaluate the VE for women aged ≥24
years. Those efficacy data should be available in 2007.

*Clinical trials* were outlined, involving 27,000 women and children on
four continents. The goal was to include broad SES and ethnic
background, sexual behavior, and concomitant disease information to
allow generalization to the overall population. Different Pap test
abnormality management also was considered, as seen in the U.S. and
around the world. Centralized cytology, biopsy processing, and HPV
typing will ensure accuracy in the end-point ascertainment (diagnoses of
HPV-related clinical disease). VE will be analyzed for preventive and
prophylactic efficacy, and post-exposure prophylaxis therapeutic
efficacy will be investigated). The validation programs were presented
for approval to regulatory authorities.

-   *Protocol 005 (P005)* involved 2391 women aged 16- 23 years old, 400
    of whom will be followed through seven years.

-   *P007* involves 1155 women aged 16-23 years old. An immune memory\
    evaluation will begin in year 5. (booster dose given at Year 5) is
    nearly complete.

-   *Future I trial of VE for CIN1/warts* involves 5442 women aged 16-23
    years.. The CIN (any grade) endpoint was chosen to evaluate the
    vaccine against the full spectrum of clinical HPV disease. CIN 1
    usually resolves on its own, but incurs high healthcare costs. VE
    for HPV-6, ­-11, ­-16, and -18 related CIN was 100%, highly
    statistically significant. Because HPV-6 and -11 significantly
    contribute to CIN 1 incidence, that VE is important to maximally
    reduce morbidity, the costs of cervical cancer screening and HPV
    disease in women. VE was 100% for external genital lesions mostly
    due to HPV-6 and -11. The study is ongoing to allow for evaluation
    of the efficacy of the vaccine over a longer period of time. The
    study is expected to end by the end of 2006. 

> *Future II trial of VE for CIN 2/3 and AIS* involved 12,167 women aged
> 15-26 years. This also could be extended, and it will be followed by a
> duration of efficacy registry study\
> in the Nordic region. A study of Norwegian HPV surveillance and VE on
> disease burden/population effectiveness will also be done. *Future II
> Results:* VE for both HPV-16 and-18 components was demonstrated a
> statistically significant difference: no cases in the vaccine group,
> and 21 cases in the placebo group. The study is ongoing to allow for
> evaluation of the efficacy of the vaccine over a longer period of
> time. The study is expected to end by the end of 2006.  In addition,
> subjects in the Nordic region will be followed for long-term duration
> of efficacy. A study of Norwegian HPV surveillance and VE on disease
> burden/population effectiveness will also be done. 

-   *Studies of prespecified prophylactic efficacy* analyses in the
    integrated database of efficacy studies were also conducted. These
    studies involved a total of 20,541 subjects who were randomized and
    received at least one dose of vaccine/placebo. This integrated
    analysis showed:

    -   100% prophylactic efficacy with respect to HPV 16- and HPV
        18-related CIN 2/3 and AIS, a highly statistically significant
        result.

    -   100% prophylactic efficacy with respect to HPV 16- and HPV
        18-related CIN 3 and AIS (include high grade cervical dysplasia,
        squamous carcinoma in situ, and adenocarcinoma in situ).

    -   100% prophylactic efficacy with respect to HPV 16- an dHPV
        18-related VIN 2/3 and VaIN 2/3, the precursors to vulvar and
        vaginal cancer.

> *A Phase III Immunogenicity trial* will involve 4800 boys and girls
> aged 9-15 years has been completed. It will be followed by a 36-month
> extension to study VE in adolescents to evaluate the duration of
> vaccine immunogenicity in this population.

-   *An efficacy study of women aged to 45 years* will be done,
    concurrently with a study of VE in 16- to 26-year-old men

The baseline characteristics of the trials' participants were outlined:
mean age of 20, most sexually active, diverse history of past pregnancy,
common use of hormonal contraception; relatively high rate of chlamydia.
Overall, \~12% (14% in the U.S.) had a diagnosis of ASC-US or worse,
suggestive of cervical intraepithelial neoplasia. Some (27%) of the
women were HPV-positive to at least one vaccine, but most were so to
only one HPV type.

There were two analysis populations: 1) per protocol, the primary
specified analysis, consisting of women naive to the relevant HPV type
at enrollment, who remained so throughout the three-vaccination regimen;
and who received the full 3 dose regimen. Case counting started 1 month
after completion of the 3-dose vaccination regimen; and 2) modified
intention to treat, consisting of women naive to the relevant HPV type
at enrollment. Case counting started 1 month post-dose. The MITT
population was the broadest possible baseline naive population. They
included people who became infected before they received the full
vaccination regimen, subjects who received only one or two doses of
vaccine, or in an non-ideal manner, or who had violated the protocols in
many different ways. VE was still 94% and 95% respectively, for CIN and
for external lesions.

*VE in women infected with vaccine HPV types.* Study data demonstrated
that women positive for one HPV type benefited from continuing VE for
the other three HPV types, at \~90% for CIN and the same for external
genital lesions. A new analysis also demonstrated VE to modify the
natural history of HPV disease. Serology and cervical-vaginal cytology
was done at Day 1 to test for active HPV infection. VE was explored for
two groups: 1) women who were seropositive and PCR negative, that is,
those who were infected before enrollment and whose immune response
cleared that infection. The study explored whether the vaccine could
induce an immune response to help prevent progression to CIN 2/3. Also
explored was 2) whether the vaccine could help women who were infected
with a vaccine HPV type but had not mounted an immune response to that
infection and 3) whether the vaccine could help women positive to both
tests, who had chronic infection and a high level of CIN 2/3. VE was in
doubt here, because these women had already mounted an immune response
and failed to clear infection.

*Results*. The vaccine was efficacious in women with evidence of
previous HPV infection but who cleared that infection. The low event
rates were consistent with the protective effect of natural immunity to
HPV. But the event rates were not zero, and 100% VE suggested an
ability to prevent recurrence of the disease caused by the relevant HPV
type. For women with early infection or who failed to mount an immune
response to the infection, GARDASIL® reduced progression to CIN 2/3 by
28% but the lower bound of the 95% confidence interval for efficacy
included 0%, so this is only a trend that needs to be evaluated
further . And as expected, the vaccine could not do much to help women
with chronic HPV infection to create further anti-HPV.

An analysis of VE for CIN 2/3, regardless of the causal HPV type was
done for two groups: 1) those who were naive to all vaccine HPV types
(no testing was done for non-vaccine HPV types), to approximate
adolescents just before sexual debut, and to evaluate VE to prevent the
development of cervical cancer overall, and 2) an "all-comer" population
of women who are sexually active and present for care. Cases were
counted immediately after vaccination for incident disease caused both
by vaccine and nonvaccine HPV types.

Preliminary data indicate a steadily rising benefit for the vaccinated
naïve group compared to the placebo group, that becomes increasingly
apparent with each screening round and resulting in a dramatic reduction
in the overall rates of CIN 2/3 caused by any vaccine HPV type. For the
second, "all-comer" population, which included women infected or with
CIN 2/3 at baseline, the same pattern emerged. While prevalent disease
is clear, the VE even for CIN 2/3 becomes visible very shortly after the
follow-up begins, and is increasingly apparent over time. The same
pattern repeated for genital warts.

The cost implications of these outcomes to health economics are evident.
Even the short-term follow-up of the Phase III studies have already
shown a significant decline in the number of women with abnormal Paps
that require a visit for colposcopy. A reduction by 20% of the 3
million annual ASC-US cases in the U.S. equates to 600,000 less tests; a
33% reduction of the 300,000 HSILs per year equates to 100,000 less
cases. The clinical trials referred women to biopsy for almost any
lesion, and a reduction was still evident. That is expected to increase
over time, as are genital biopsies and genital definitive therapy.

The Phase III program will end early. When the overwhelming VE was
demonstrated with a favorable safety profile, the DSMB mandated that
women in the placebo groups receive accelerated vaccination.

The finding of 100% efficacy precluded the ability to find an immune
correlate of efficacy. With no breakthrough cases due to waning
immunity, the minimum protective anti-HPV level could not be determined.
However, the results after 48 months of follow-up showed persistent
anti-HPV levels. These declined to a plateau level paralleling the
anti-HPV levels in women who are seropositive and PCR negative at
baseline from a natural immune response that cleared HPV infection.
Additionally, the 100% VE determined against persistent infection and
HPV-16 related CIN 2/3, with no breakthrough infections, reflects well
upon long-term protective efficacy. The Scandinavian population-based,
long-term follow-up will assess that. The women enrolled were vaccinated
in 2002; U.S. vaccination is expected to begin in June of 2006. The
Scandinavian cohort will be a good sentinel cohort, and will be analyzed
over time for breakthrough infections. That will inform any possible
need for booster doses.

Finally, Merck explored whether anti-HPV levels are needed to protect
against infection and disease or if, like hepatitis B, a vaccine might
just induce a strong anamnestic response that aborts disease even in the
absence of detectable serum anti-HPV. Merck followed the 24% of women in
the trials who vaccinated, mounted high anti-HPV 18 levels, but then
nominally sero-reverted by Month 24. High levels of protection remained
for HPV-18 related disease when followed over six-month intervals, even
in the 24% of the population who had no detectable anti-HPV-18. That
suggests long-term vaccine protective efficacy and a potential
anamnestic response, and the latter is the sign of long-term vaccine
efficacy.

Also interesting is that pre-adolescents seemed to mount an immune
response even more intense than that of the adults. Recent data of
sentinel adolescent cohorts also show adolescents' immune response
remaining much higher than that seen in adults, even a year after the
vaccination regimen. That is important because month 18, one year after
dose 3, is the where the plateau begins.

An analysis was done to evaluate whether administration of one dose of
vaccine in women who are seropositive at baseline will induce an
anamnestic response. These women had much higher anti-HPV levels two
months after dose 1 than women who were baseline naïve, and given the
two-month lapse, that could even be an underestimation of the initial
high anti-HPV level in such women. A mechanistic study is now underway
to see if a long-term administration of a dose at five years after
enrollment provides the same kind of anamnestic response. Preliminary
data are encouraging that these vaccines can induce memory immune
responses that are highly active and result in a robust reconstitution
of anti-HPV levels, indicating likely long-term protection.

*Safety data* were shared from a cohort of 27,000 enrolled women,
divided into groups receiving monovalent vaccines or other quadrivalent
vaccine formulations, and those receiving GARDASIL.® Serious adverse
event rates were very low, at 0.5% for the other vaccines versus
GARDASIL's ® 0.4%. Women in both groups recorded events on their vaccine
report cards. Serious vaccine related adverse events were rare and the
discontinuation rate was extremely low. Systemic events were comparable.
Injection site adverse reactions were slightly higher in the GARDASIL®
group, but half of those were from the injection itself, and were
comparable to the reactogenicity seen with other adolescent vaccines.
Rates of fever were slightly higher in the GARDASIL group, but most were
very low grade; very high-grade temperature rates were the same to
placebo.

Children aged 18-26 years, 9-17 year-old girls and 9-15 year-old boys
received GARDASIL, and were compared to adult women. Injection site AEs
were lower in the children, as were systemic AEs, while serious AEs were
comparable. The safety profile appeared to be unaffected by the baseline
HPV status of the recipient.

Pregnancy outcomes evaluated included medical history during the
pregnancy, mother and child's outcomes in the neonatal period, causes of
spontaneous abortion, and elective termination were all examined.
Infants were followed to the end of the study to look for late events
not detected in the neonatal period. Natural history studies of
pregnancy in which pregnancy screening with beta-HCG is used indicate
rates of spontaneous abortion at 15%-20%, but the clinical trial's use
of beta-HCG screening found rates of 28%-33%. Congenital abnormalities
occur in \~3%-4% of live births in the general U.S. population.

Approximately10% of subjects became pregnant during the trial, even
though subjects were instructed to use contraception during the
vaccination phase of the study. Of the known outcomes (those "unknown"
had just not given birth when the database was closed) live births were
predominant, with rates comparable between the two vaccination groups.
In terms of pregnancies that began close to vaccination versus
pregnancies ≥30 days of vaccination, the normal-baby outcomes were
comparable, as were spontaneous losses. Rates of both elective and
spontaneous abortions within 30 days of a vaccination were slightly
lower in the group that received GARDASIL® compared to the placebo
group.

The rates of congenital abnormalities were comparable to those in the
general population and similar between the GARDASIL® group (15) and the
placebo group (16). But the distribution was slightly different; five
cases occurred within 30 days of the vaccination of the GARDASIL® group,
and none in the placebo group; and the opposite occurred for those
becoming pregnant ≥30 days after vaccination, with ten in the GARDASIL®
group and 16 in the placebo group. The five cases involved common
congenital anomalies associated with late fetal injury far after
vaccination. Merck's developmental and reproductive toxicology
preclinical modeling also showed no association of congenital anomalies
to GARDASIL® vaccination, even during pregnancy and even at the most
vulnerable period. The DSMB, study steering committee, and an expert
teratologist were in consensus that GARDASIL® does not impact pregnancy
outcomes in any way.

Post-licensure evaluation includes a large pharmacovigilance program
involving 35,000 women. It will monitor general safety and pregnancy
outcomes, establish pregnancy registry, and evaluate long-term efficacy.
Through the central Nordic registry, long- and short-term efficacy and
safety will be evaluated on a population basis in real time.

*Discussion* of the presentations to this point included:

-   The SAE rate for those PCR negative was 0.6, but twice that for
    those PCR positive. The SAE rates, particularly in the seropositive
    population, were multiple events that were not vaccine related
    (e.g., motor vehicle accident, sports injuries), presenting no
    signal.

-   *Since teenage girls develop genital warts earlier than males, are
    they not the transmission route to young men?* The answer lies in
    data on the age of the young women's first partner for their sexual
    debut. The partner is typically substantially older and more
    experienced than the girl. A survey in Iceland indicated on average
    a three-year older partner. Transmission is probably back and forth,
    but for herd immunity, vaccination of men will be important for HPV.

-   *The bridging to age groups was done based on serum antibody from
    vaccine administered intramuscularly, but natural infection produces
    little serum immunity. Given that, is that a good correlate of
    efficacy?* Dr. Barr defined the bridging as a standard approach for
    many vaccines to examine populations in which efficacy cannot be
    measured, compared to populations in which efficacy is demonstrated.
    The only other way to definitively show this will be through very
    long-term, efficacy data. But the fact that the vaccine-induced
    anti-HPV responses were higher in children than adults, where the VE
    was definitive, satisfies the prerequisites to bridge that VE to the
    younger population. Dr. Dubin agreed, and added that the role of
    serum antibody in protection is proven by preclinical animal studies
    showing passive antibody transfer to other animals who then resisted
    challenge. Additionally, most of antibody in cervical secretions is
    transudated from serum antibody. Measurement of cervical antibody
    levels is not feasible, both from a collection standpoint and due to
    no standardized methodology for measuring cervical secretion
    antibodies. Those considerations support the use of serum antibodies
    as a reasonable measure of the immune system element that mediates
    protection, particularly since the vaccine study data indicate that
    the cervical antibody levels will correlate reasonably well with the
    serum levels.

-   Dr. Dubin commented that data on HPV incidence or prevalence
    indicate that oncogenic HPV infections have some relationship to age
    at infection. The highest rates are among younger women and they
    drop with age. Whether this pertains to less exposure in women aged
    \>25, or to partial protection that\'s acquired from previous
    exposures, is unclear. Either way, although the absolute rates are
    lower in older women than those younger, new incident infections
    occur; and the overall absolute risk continues even with older age.
    Dr. Barr agreed. Merck's Phase III database showed the highest
    infection incidence in 18-year-olds, that that slowly declines with
    age. But no data can indicate whether age of receipt changes VE; all
    that is known from current data is that the VE is comparable
    regardless of the age of the recipient.

-   Dr. Barr reported that antibody levels were somewhat higher among
    people who were PCR positive but serologically negative, but not as
    dramatically high as among the baseline seropositives.

-   Dr. Plotkin asked Dr. Lowy for his opinion of whether an L1/L2
    vaccine might provide additional breadth of immunity. He answered
    that in vitro studies show that the L2-only vaccine can induce
    cross-neutralizing activity, but at substantially lower titers than
    with the L1-VLP vaccine. The immunodominance of the L1 vaccine
    causes animals, exposed to L1/L2 VLPs, to be essentially naïve to
    the L2. L2 has not been used in human clinical studies.

-   Dr. Martin Meyers asked Dr. Dunne if there was any chance that the
    2.4 prevalence rate in children aged 6-11years might come from
    maternal infection, or early sexual encounter. She could not say,
    since these data were from NHANES, which does not collect data on
    sexual risk or other exposure.

-   Since the antibody concentrations after the three-dose schedule are
    so much higher than those from natural infection, Dr. Georges Peter
    if consideration was given to a two-dose primary schedule, or one
    dose that is boosted five years later. Dr. Dubin responded that the
    significant rise in antibody titers at the third dose, greater than
    that after the second dose, also suggests that two doses do not
    convey the maximum immune response. That level may still be
    protective, something that could be shown if a correlate of
    protection is ever developed. For now, the overriding consideration
    has been the greater duration of protection afforded by such a
    significant boost, something important in a vaccine to be given down
    to age ten years or even younger.

-   Dr. Abramson asked what Merck would seek in its FDA licensure
    application as regards issues of pregnancy, since many recipients
    could potentially be pregnant. Dr. Barr said that Merck states that
    pregnancy should be avoided during the course of vaccination, and
    then provides all the information on the vaccine. There are no data
    on the use of this vaccine in pregnant women. For that reason, they
    would recommend that FDA label the vaccine as Pregnancy Category B,
    to avoid the use during pregnancy, and allow flexibility in the
    dosing regimen to accommodate pregnant women.

    ***Cost Effectiveness of HPV Vaccination***

Presenter: Dr. Harrell Chesson, Division of STD Prevention

> Overview: Ongoing and published cost-effectiveness studies of HPV
> vaccination in the United States.

Models are important in evaluating the cost-effectiveness of HPV
vaccination, because many factors affect the costs and benefits of HPV
vaccination, such as: vaccine efficacy, coverage and duration, HPV
infection natural history, rates of HPV transmission, and cervical
cancer screening factors such as coverage and frequency. Many of these
factors are unknown or not known with precision at this time. Models are
the only way to take these factors into account and project the possible
impact of HPV vaccine.

The literature on HPV vaccine cost-effectiveness (CE) has used Markov
models (also called cohort models or health-state transition models) of
the natural history of HPV infection. HPV transmission, and occasionally
the natural history of HPV infection, are addressed with dynamic models.

The advantages and disadvantages of each were outlined. Since the Markov
models do not include HPV transmission effects (or herd immunity), they
are not as useful when the effect of transmission is important (e.g.,
cost/benefit of adding males to a female-only vaccination program).
Leaving out the transmission effects could understate the vaccination's
benefits. However, the Markov models may be able to establish a
reasonable upper bound of the cost per quality-adjusted life-year (QALY)
gained by vaccination.

Dynamic models do include HPV transmission effects, or herd immunity, so
they can better evaluate vaccination scenarios in which transmission
effects are important. But, while the inclusion of transmission may make
them more realistic, it also introduces additional uncertainty from
parameters such as sexual-mixing behaviors and transmission
probabilities.

A Markov model of the natural history of HPV infection was shown. It
plotted a person's movements from one state of health to another at
defined and equal intervals, or Markov cycles. The probability of
transition can be made dependent on characteristics such as age. The
dynamic compartmental model of HPV transmission places the population
into a few compartments (e.g., vaccinated, susceptible, infected) that
can then be further stratified based on characteristics such as age,
sex, and sexual activity level. The rate at which persons move from
compartment to compartment can be a function of many factors (e.g.,
moving from susceptible to infected depends in part on HPV prevalence).
Differential equations are used to model the spread of infection over
time.

*Markov models.* Three studies using the Markov model to evaluate the CE
of HPV vaccination in the U.S. were outlined:

-   Sanders and Taira (*Emerging Infectious Diseases,*2003;290:37-48)
    examined the benefits of adding an HPV vaccine to current U.S.
    cervical cancer screening. They assumed that 71% of women were
    screened every two years. Their model examined a vaccine targeted
    against high-risk HPV types in general. In the base case analysis,
    age of first vaccination was 12 years; vaccine coverage was 70% and
    VE was 75%. Female-only vaccination was estimated to reduce cervical
    cancer incidence in the vaccinated cohort by 20% at a cost per QALY
    of \$22,800; with a lifetime duration of protection, the cost per
    QALY was \$12,700.

-   Goldie et al (*Journal of the National Cancer Institute*,
    2004;96:604-615) examined the benefits of adding a vaccine for
    HPV-16 and -18 to the current U.S. cervical cancer screening. The
    assumptions about current screening practices were based on reports
    that 67% of women were screened within one year, 28% had been ≥1
    year since their last screening, and 5% had never been screened. In
    the base case analysis, age of first vaccination was 12 years;
    vaccine coverage was 100%, and VE was 90% Vaccine duration was
    lifelong and the vaccination costs was \$377 per series *Results:*
    Cost per QALY gained for female-only vaccination was \$24,300. As VE
    rises from 70%-100%, the 46% reduction in the lifetime risk of
    cervical cancer increases to 66% and the cost per QALY drops from
    \~\$33,000 to \~\$20,000.

-   Kulasingam and Myers' model also examined a vaccine targeted against
    high-risk HPV types in general. In the base case analysis, age of
    first vaccination was 12 years; vaccine coverage was 100% and VE was
    90%, with a 10 year duration of protection. This study focused on
    the cost per life-year gained rather than the cost per QALY gained.
    They found the most CE strategy costing \<\$50,000 per life year
    gained to be vaccination plus biennial screening, delayed until age
    24 years. That resulted in \~\$45,000 per life-year gained, compared
    to a strategy of no vaccination and screening every three years
    beginning at age 18.

In the sensitivity analyses across the Markov model studies, the cost
per QALY gained for female-only vaccination ranged from \<\$10,000 to
\>\$100,000. The CE estimates were most sensitive to cervical cancer
screening issues such as frequency and age of initiation, but the
duration of VE also impacted the CE. The CE effectiveness estimates were
least sensitive to reasonable changes in the natural history parameters
and the screening test characteristics.

*Dynamic models.* The dynamic model used by Taira et al. (*Emerging
Infectious Diseases* 2004:10(11):1915-23) examined vaccine targeted to
HPV-16 and -18 with 90% efficacy. The Merck modelers, Elbasha and
Dasbach (in progress) examined a quadrivalent vaccine with 90% efficacy
against low-risk types and 70% efficacy against high-risk types.

Both models assumed vaccination at or before age 12 years with 70%
vaccine coverage. The vaccine duration ranged from ten years to
lifetime; vaccination cost per series was \$300-\$500.

Merck's model set a per-partnership HPV-transmission probability of 0.8
for male to female transmission and 0.7 for female to male. The
frequency of annual cervical cancer screening ranged from 0.6%-60.4%,
varying by age. The study population was divided into 15 age groups and
three sexual activity groups, the latter based on rate of new sex
partners per year. There was assortative mixing, meaning that sex
partners are more likely to be of similar age and sexual activity level
than would be expected if partners were selected randomly. The QALY cost
for two strategies was charted: no vaccination and cervical cancer
screening only, and addition of female vaccination to the screening
program. The cost per QALY gained of adding female vaccination to an
existing cervical cancer screening program was \$728. The Merck model
posited an 8% reduction in steady-state cervical cancer incidence for
those aged ≥12 years, with a ten-year duration of immunity, and
incidence reduction rose to \~35% with a lifetime duration of immunity.

The Taira model was a hybrid dynamic-Markov model. While the dynamic
model generated HPV incidence estimates, the Markov model was used to
convert the incidence estimates to QALYs and costs. The assumed
per-partnership transmission probability was 0.35 for the youngest age
groups, which decreased gradually to 0.15 for the oldest group. The
population was divided into nine age groups and four sexual activity
groups, with assortative mixing by age and sexual activity level. The
cost in QALYs again was charted for no vaccination and screening only,
and female vaccination added to screening. Again, the latter increased
the total cost (by \$244 per woman) but it also increased QALYs by .0167
per woman (or 6.1quality-adjusted life-days), yielding a CE ratio of
about \$14,500 per QALY. This model showed a 62% reduction in the
lifetime risk of cervical cancer and a 95% reduction of lifetime
cervical cancer cases related to HPV-16 or -18 in the vaccinated cohort.

The cost per QALY as estimated using the Markov models
(\$22,000-\$24,000) exceeded that of the dynamic models (\$700-\$14,600)
in part because the Markov models excluded the benefits of herd
immunity. Additionally, the Merck model's lower cost per QALY is
attributable in part to the inclusion of the benefits of preventing
HPV-6 and -11. However, these are base-case estimates, and the estimated
CE ratios can vary substantially when base-case assumptions are varied.
The limitations of the models must be considered, including the
uncertainty of HPV transmission dynamics, the duration of naturally
acquired immunity, and the non-inclusion of all possible vaccination
effects (e.g., possible decreased positive predictive value of the Pap
with rising vaccination coverage). The models do not consider that AEs
may incur cost or reduce QALYs; that vaccination may affect sexual
behaviors or health-seeking behaviors; or the prevention of other
HPV-related cancers besides cervical cancer. Including the benefits of
reducing other HPV-related cancers would improve the estimated CE of
vaccination, as would the inclusion of averted indirect costs such as
productivity loss due to cervical cancer. It is possible that small
changes in a large number of parameter values could affect the results;
as such more comprehensive sensitivity analyses may be warranted.
Finally, future studies will further examine the CE of male vaccination
and other factors affecting vaccination CE, such as age at vaccination
and catch-up vaccination.

***Mathematical Modeling of HPV Vaccine***

Presenter: Dr. Geoff Garnett, Imperial College, London

> Overview: Impact of HPV vaccines, considering transmission dynamics
> and disease progress, modeled in two ways; one focusing on the
> interaction between HPV types and cervical cancers and the other
> focusing on age of vaccination and catch-up programs.

Modeling was presented of a quadrivalent HPV vaccine delivered in the
setting of routine cervical cancer screening. The model included the
natural history of HPV infection and disease, estimated parameters and
calibration, vaccine impact on cervical cancer, precancerous
abnormalties and genital warts, the impact of vaccinating women alone
versus both genders, duration of vaccine-derived protection, and age of
vaccination and catch-up programs. Inclusion of coinfections could make
the model complex beyond utility.

A modeling framework was shared to describe HPV-16's and -18's natural
history process, delineated to precancers, neoplasias, and three types
of lesions. The model's focus was on CIN2 LSIL and HSIL, considering
both screening and natural regression of infection (transient
infection), and effective treatment of chronic infection, through to
stage four cervical cancer and death. For HPV-6 and -11, which lead to
lesions and warts rather than cancer, the model assumed a population of
infected susceptibles who are vaccine protected, or not. The latter
would be either asymptomatic or symptomatic with warts, which could
either regress back to an asymptomatic stage, recur, or reach immunity.
Another variable considered was loss of vaccine protection leading to
renewed susceptibility. Type-specific natural immunity of five years,
and then lifelong, was assumed.

The model was calibrated based on data on sexual behavior and age of
sexual debut reported by the National Survey of Family Growth, which was
compared to observed prevalence of HPV infection (Marhart et al, 2005)
as well as to SEER mortality data. Future analysis will include
age-specific patterns of infection and disease.

High transmission probabilities per sexual partnership were required to
generate the observed prevalence of HPV infection, and cohort studies'
observed mean durations of acute infection were used. The baseline
no-screening model inserted the HPV type-specific proportions of
cervical cancer incidence which, when combined, produced \~ 12/100,000
deaths annually. Screening was then introduced to the model and
increased over 30 years to a high coverage of 85% of women screened
biannually. Shortening the period of chronic infection decreased the
prevalence of infection; and since chronic infections are also
infectious, HPV transmission was also reduced. Then, with vaccine
introduction, vaccine-type HPV decreased. The rates of decrease differed
due to each type's different basic reproductive characteristics. Those
with a lower reproductive rate are more sensitive to reductions in the
duration of infection.

Declines in mortality, LSIL and HSIL were charted, based on the same
assumptions of 70% vaccine coverage among women and 85% coverage of
biannual screening. Two scenarios were charted: a worst-case scenario
where vaccinees stop screening (assuming they are protected) and a
best-case scenario of rising reductions in cervical cancer cases and
deaths due to screening, assuming lifelong vaccine protection.

For LSIL and HSIL combined, screening detection reduced cases per
100,000 screened women from \~350 to \~100-150. More analysis of the
difference between high- and low-grade incidence is needed, which
stemmed from the duration of naturally-acquired immunity or the
difference between modeled and actual screening. More work also is
needed to determine why the model's assumptions produced a dramatic
increase in the age-specific patterns of disease and prevalent lesions
with older age. Adding 70% vaccination of men to the model produced
additional decreases (\~16%) in mortality among women, as the
vaccination of men reduced the transmission of HPV from men to women.

The impact of vaccine without boosters was charted, comparing no
vaccination to lifelong and ten-year protection. The latter was divided
between screened vaccinees and vaccinees that drop screening. With
screening, the 10-year duration of protection group had a lesser
reduction in mortality than those with presumed lifelong protection, but
still a reduction. With 10-year duration of protection, vaccinees who
drop out of screening had an increase in mortality compared to the
scenario of no vaccination.

A model was described which addressed the age of vaccination and use of
catch-up programs. This deterministic model assumed 100% lifelong
duration of naturally- and vaccine-derived protection, and
compartmentalized women and men in a susceptible-vaccinated-immune
structure. Younger adults to age 44 years were stratified by age in
weeks. The HPV transmission probability was estimated by comparing the
model's prevalence at different times to observed data for HPV-16
prevalence in the age groups. Sexual debut by a percentage of the
population was presumed by a given age.

For 70% vaccine coverage at ages 12, 15, and 18 years, the charted data
indicated that vaccinating older age groups would have a more immediate
impact on outcomes such as LSIL, HSIL, and cervical cancer. The more
immediate impact arises because those in the older age groups are more
likely to be sexually active, allowing vaccination to affect infection
spread patterns immediately. But over time, vaccinating the younger
population has a bigger impact; charted data showed 72% of HSIL cases
prevented by 2050 with vaccination at age 12, versus 67.5% at age 15 and
51.4% at age 18. With added vaccination of males, those proportional of
cases prevented by 2050 rose to 84.9%, 79.9%, and 60%, respectively. The
same pattern resulted for invasive cervical cancer cases, with
vaccination at 12 providing the biggest impact over the long term. The
same scale was seen with additional vaccination of males.

Catch-up programs were also analyzed, defined as accomplishing coverage
across the desired age groups immediately on program roll-out. In this
case, the model assumed vaccination of all 12-, 13-, 14-, and
15-year-olds, to reach a wider proportion of the sexually active
population at once and to reduce infection spread, followed by
vaccination of 12-year-olds thereafter. Again, the charted data showed
the greater effect of vaccinating at the younger age, before the
sexually active period, and a similar pattern was seen between HSIL and
cervical cancer cases prevented.

Data were then graphed assuming a 12-year-old vaccination program,
followed by catch-up vaccination programs at 3-, 6-, 9-, and 12-year
intervals after vaccination. Diminishing returns were apparent with the
increasing ages involved in the catch-up program, which was related to
the proportion already infected when vaccinated. Catch-up vaccination
done up to 6 years after initial vaccination at age 12 (i.e., age \~18,
or even 21) would produce an effect, to prevent another \~12%-20% of
cases, but there was little effect thereafter. The same pattern was true
for cervical cancer cases.

Finally, modeling the ages at vaccination assuming a ten-year duration
of protection (and no booster) showed a tradeoff between the benefit of
early vaccination, pre-sexual debut, versus the lost vaccine protection
at the older and still sexually active ages. Nonetheless, vaccinating
12-year-olds remained the best long-term strategy, although the benefit
was not as large. Adding a booster again increased reductions in disease
incidence.

***Behavioral Issues Related to HPV Vaccination***

Presenter: Dr. Nicole Liddon, Division of STD Prevention

Overview: Possible sexual behavioral issues resulting from HPV vaccines.

Concerns have been expressed that an unintended consequence of HPV
vaccine could be increased sexual risk behavior among vaccinated
adolescents believing they are protected from an STD. That concern could
influence vaccine implementation, if only due to parental fear of an
increase in their child's sexual risk, and pediatricians' reactive
reluctance to even raise the issue.

Behavioral disinhibition is defined as an increase in unsafe behaviors
in response to perceptions of safety caused by introduction of a
preventive or therapeutic intervention. This is not a new concept. There
have been concerns about sexual disinhibition related to the use of
anesthesia in childbirth and increased sex within marriage, and to
increased sexual risk if penicillin were used to treat syphilis. Today,
issues of needle exchange programs and condom use continue such
discussions.

YRBS data indicate that 7.4% percent of children from grade 9 through 12
have had sex before age 13; \~33% of 9th graders are sexually active,
rising to \~66% by 12th grade. Of all 9th grade (not just those sexually
active) 10.4%, have had four or more sex partners, as have 20.3% of all
12^th^ graders. Data from the National Survey of Family Growth are
consistent with those findings. By age 15, \~25% of both males and
females have had vaginal sex, rising to \~70% percent by age 18 for
females and 19 for males. Clearly, these data point to a need for
vaccination in early adolescence, before sexual initiation and multiple
sexual partners.

The underlying hypothesis to the concern about disinhibition is that
fear of HPV will motivate abstention from sex or at least prompt safer
sex behaviors. Some of the factors influencing initiation of sexual
activity were outlined. These indicated that the decision to have sex by
adolescents is based on multiple and layered influences by family, peers
and even school and community factors. It is rarely related to a single
factor, such as HPV risk. In fact, NSFG data reveal that 15-19 year-old
virgins' fear of an STD (including HIV) was only cited by 10% percent of
males and 7% of females as a reason not to have sex.

Data from Merck\'s HPV vaccine clinical trials, emergency contraception,
and condom-availability programs (CAP) were summarized to address the
issue of sexual behavioral disinhibition among adolescents.

-   The Merck data of new male sex partners per person-year among North
    American women showed no increase in new sex partners per
    person-year after enrollment in the HPV vaccine trial, compared to
    self-reported activity beforehand.

-   Data from three randomized trials looking at young, sexually active
    women who attend healthcare clinics for reasons not related to
    emergency contraception, showed no differences between intervention
    (provided contraception) and control groups.

-   Data from the impact of CAPs includes both sexually active and
    sexually inactive U.S. adolescents. Overall, the studies show no
    significant change in the percentage of young people who have ever
    had sex, after having condoms available, or between schools that
    have CAPs and those without.

*Conclusion*. Adolescent sexual behavior onset indicates early
adolescence as the best time for HPV vaccine delivery. Various studies
suggest that disinhibition will be unlikely to result. Sexual
disinhibition is measurable and can be monitored, something being
considered by the CDC and others (e.g., through NSFG and YRBS data
collection).

***Options for ACIP Recommendation on HPV Vaccine***

Presenter: Dr. Lauri Markowitz, Division of STD Prevention

> Overview: Additional considerations by the HPV Working Group for
> vaccine recommendations, for discussion at the June ACIP meeting.

The Working Group has focused on developing recommendations for use of
the quadrivalent vaccine based on several assumptions: 1) the possible
mid-2006 U.S. licensure of the quadrivalent vaccine for HPV-6, -11, ­-16,
-18, and 2) its later licensure for use in males (pending data on
efficacy for prevention of infection or disease in males). Also assumed
is 3) that GSK's bivalent HPV-16/18 vaccine will be licensed for use in
females at a later date.

A variety of background information needs to be considered for
recommendations. This includes data on vaccine and clinical trials,
burden of HPV related disease and epidemiology, sexual behavior, vaccine
acceptability, programmatic issues and impact and cost effectiveness.

Data from the clinical trials show that very high VE in 16-26 year-old
females against the clinical trials' vaccine-HPV type end points;
protection has been shown through 2½-31/2 years after dose 3; and the
vaccine is safe, with only minor injection site pain reactions.
Postvaccination seroconversion rates in 9-26 year-olds substantially
exceed those achieved after natural infection, and are highest in those
vaccinated at younger ages. Antibody titers decline over time after the
third dose, but plateau by 18 months, remaining higher than those after
natural infection for several years.

Among the unknowns are a serologic correlate of protection (due to the
trials' high efficacy), the duration of protection or need for a
booster, and missing data on efficacy among males. There are also
knowledge gaps about HPV infection and natural history that might impact
vaccination.

*Duration of protection* is unknown for any new vaccine when first
licensed. The quadrivalent HPV vaccine has some similarities to
hepatitis B vaccine that may be instructive. Both are subunit vaccines
with an alum adjuvant. Hepatitis B vaccine provides long-term
protection, and although antibody titers wane in some individuals who
receive hepatitis B vaccine, exposure/infection with hepatitis B usually
does not result in chronic carriage or clinical disease. Direct
comparisons are limited by the fact that hepatitis B is a systemic
infection while HPV is mucosal or cutaneous. Questions have been raised
concerning whether an anamnestic response will protect individuals from
persistent HPV infection and sequelae. Clearly follow-up studies are
needed to monitor duration of protection from HPV vaccine .

Other background information for recommendations also considered by the
Working Group includes was outlined. *Vaccine acceptability* is
relatively high among providers and parents, but more for vaccination of
older adolescents. Education about and recommendations from professional
organizations could further acceptability.

*Cost Effectiveness* -- Models for impact and cost effectiveness of HPV
vaccine are complicated due to the multiple HPV types, complicated
natural history, and the long time between infection and health
outcomes. The vaccine will not negate the need for cervical cancer
screening, since HPV other than the vaccine types cause \~30%  of
cervical cancers. The models evaluated the impact of HPV vaccine in the
setting of cervical cancer screening.

Both the Markov and dynamic models show that high HPV vaccine coverage
could prevent most vaccine-type-associated cancers and precursor
lesions, reducing the 10,000 annual cervical cancers in the U.S. by
\~70%. While the impact on cervical cancer will not be seen for many
years, the impact on precursor lesions will be seen sooner.

In the Markov models cost effectiveness has been approximately
\$24,000/QALY for bivalent HPV vaccine in females -- with wide range in
sensitivity analyses. In dynamic models, which include impact of herd
immunity, the vaccine appears more cost effective. Work is ongoing using
dynamic models to further evaluate the impact and cost effectiveness of
quadrivalent vaccine.

The Working Group's possible recommendations for the ACIP to consider in
June include:

1.  Recommendation for routine vaccination of females aged 11-12 years
    with three doses of quadrivalent HPV vaccine. The vaccination series
    can be started as young as nine years, at the discretion of the
    physician. (This depends on the FDA's indication of the lower age of
    vaccination.)

    a.  The rationale in support includes HPV infection's high
        prevalence, the inability to target high-risk groups, and the
        modeling showing more impact with routine vaccination.

    b.  This strategy would result in vaccination of more females before
        sexual debut, resulting in greater prevention impact.
        Implementation of a three-dose schedule at this age is also
        aided by the fact that other vaccines are recommended at this
        age and a young adolescent healthcare visit is recommended by
        professional organizations.

    c.  There is no evidence of waning immunity and ongoing studies will
        monitor duration.

2.  Upon vaccine introduction, there will be unvaccinated older females
    who could benefit from the vaccine, and FDA approval through age
    26 years is expected. The options to vaccinate 13-26 year-olds
    include:

    a.  Vaccination of all females aged 13-26 years who are not been
        previously vaccinated.

    b.  Permissive recommendation for all age groups with a specific
        recommendation for a more limited age range.

    c.  Further modeling will be done and discussed for this age group.

3.  Vaccination of males. It is expected that licensure will be at a
    later date, when there are efficacy data in males. Possible initial
    ACIP statement wording could be similar to, "HPV vaccine is not
    licensed for use in males. Studies in males are under way and
    results are awaited."

The Working Group will continue discussion of the quadrivalent vaccine
recommendation options, and modify them as needed after the FDA
licensure. The draft recommendations and options will be circulated
before the June ACIP meeting. Future discussions will develop
recommendations for the bivalent HPV vaccine.

*Discussion* by the committee of the HPV presentations included:

-   The main arguments against recommendations to immunize to age 26
    involved feasibility more than any other issue (e.g., to catch up)
    and still-incomplete cost effectiveness data.

-   Dr. Lieu asked about the sensitivity of the CE analysis to the cost
    of vaccine, and how likely the analysis' costs will match the
    vaccine cost. Dr. Chessen answered that the analysis is sensitive to
    vaccine cost, since that is a large part of the cost per QALY. In
    some cases, doubling the vaccine cost more than doubles the cost per
    QALY. Dr. Feinberg reported that Merck has not yet determined the
    vaccine's cost. But relevant data are continuing to emerge and are
    expected to make the true value of the vaccine apparent. The latter
    needs to be stated to provide the context when the vaccine price is
    announced.

-   Dr. Hull observed that low SES, undereducated women will not be
    vaccinated without a mandate, and they are the same group that
    disproportionately dies from cervical cancer. He asked what effect
    those factors had on the models' highest risk populations. Dr.
    Chessen responded that that issue has less impact in a CE analysis,
    because many of the vaccine's benefits involve reducing the
    follow-up costs after screening. But it would affect cervical cancer
    incidence, and he hoped to add that into the analysis later.

-   Dr. Chessen confirmed for Dr. Finger that the averted medical costs
    were included in the CE analyses. Some of the papers did not provide
    a breakdown of the benefits, but he offered to get that from the
    modelers.

-   Dr. Gall supported beginning the vaccine's use at age 11 or 12, but
    added that vaccination for females aged 13-26 who were not
    previously vaccinated is also critical. ACOG could not support a
    recommendation for this vaccine only for pediatric use. Just one
    reason for that was that solely pediatric use would provide no
    impact on cancer prevention for \~25 years.

-   Dr. Sam Katz observed that almost all the studies presented related
    to the U.S., and asked what modeling had been done for resource poor
    countries without cancer screening. Dr. Garnett reported a lot of
    work on that, particularly by Dr. Goldie, under a grant from the
    Gates Foundation and the WHO. She is collecting data and studying
    the vaccine's impact in India, Latin America and other resource-poor
    areas. The results for the U.S. were presented "because that is
    where we are."

-   Dr. Traenor commended this as the most informative session he had
    ever attended in discussing the pro's and con's of a vaccine. He
    asked what the assumptions were, in the scenarios of low vaccination
    rates in women, about the VE of vaccinating men. Dr. Garnett
    reported that the assumption was of similar effectiveness against
    acute infection in men as seen in women ─ a very high efficacy.

-   Dr. Pickering asked about vaccine availability. Dr. Feinberg
    reported that Merck had invested significant resources to ensure its
    availability for all indicated cohorts in the label for the first
    years of use. Dr. Monteyne reported the same as true for GSK.

-   *Bridging .* Dr. Martin Myers asked FDA's opinion of the correlation
    of immunogenicity between the 9-15 year-old female age group to that
    in males, as a surrogate marker. Dr. Baylor responded that it was
    too early in this vaccine application's review to comment on that.
    Dr. Powell asked why the bridging data could be applied to young
    adolescent females but not males.

    -   Dr. Markowitz responded that the 9-15 year old females could be
        bridged to VE in older females, but there was no such parallel
        group for the boys.

    -   Dr. Barr added, from Merck's perspective, that the 100% VE,
        slightly higher immunogenicity found in boys, and the same type
        of hair-bearing, keratinized skin around the genitalia of both
        sexes, supported male vaccination. That also would provide the
        benefits of herd immunity to controlling infection.

    -   Dr. Peggy Reynolds demurred, noting that not only is efficacy
        not shown for males, but also that females are protected from
        cervical cancer by transudated IgG.

    -   Dr. Dubin cautioned that the genital herpes vaccine trial showed
        differences in gender-based efficacy, despite the similar
        distribution of genital herpes lesions in men and women to that
        of genital wart lesions. That could be applicable to the
        questions about the relevance of bridging.

    -   But Dr. Barr disagreed, calling that speculation. He added that
        the objective is not only to prevent cervical cancer, but RRP,
        genital warts (for which the vaccine is 100% effective on
        women's external genitalia), and other cancer burdens that HPV
        can cause. Although the organs are different, the skin is the
        same, as is the natural history, HPV types, treatment and
        efficacy. He urged vaccination of males to avoid the limitations
        of a gender-specific policy and to broaden the vaccine's
        availability to all.

-   Dr. Temte asked about cost effectiveness considering the incremental
    costs with male vaccination added, and whether that would make it so
    expensive as to prevent a recommendation. Dr. Chesson could only
    report that the range of costs per QALY is great across the only two
    studies that address this question. CDC is trying to figure out now
    why that is.

-   Dr. Schuchat noted that the models assumed the stability of other
    HPV types. She asked if there was any reason for concern about
    replacement types, particularly as regards the herd immunity being
    modeled. Dr. Garnett reported that was included in the analysis. The
    concerns were that removing the progress to disease can invite
    replacement by other types; and that this could create a niche for
    the other types by removing the natural cross immunity. That will be
    studied in Finland. But evolutionarily speaking, the HPV types are
    \~10% different in genotype, and 2% different even within types,
    making them fairly stable. This is an important issue. Additional
    immunity created by the vaccines, which is not conveyed by natural
    infection, is also possible and being studied. Dr. Barr added that
    the HPV-16 vaccine trial showed comparable disease rates caused by
    the four types. He also noted that women infected with one type are
    at higher risk for another and thought a replacement phenomenon to
    be highly unlikely.

    -   Dr. Renee Jenkins, of the National Medical Association, pointed
        out that access to this vaccine for eligible children would be
        through the VFC program, which is already under strain. Dr.
        Lance Rodewald reassured her, though, that by statute, VFC
        coverage is mandatory spending and the funding will be
        available. However, the Section 317 funding is discretionary,
        and more of a concern.

        **PUBLIC COMMENT**

Dr. Bobbi Gostout, Associate Professor at the Mayo Clinic, attended to
represent the Society of Gynecologic Oncologists. She had no
vaccine-related conflicts to declare. She stated the importance that the
ACIP hear from physicians serving the women who still develop cervical
cancer, even in highly screened populations. There are no easy
solutions; some women cannot or will not avail themselves of care; some
do not understand the importance of screening; and some rely on a Pap
test result that turns out to be a false negative. HPV vaccine provides
hope for all those categories and most promisingly, it would reduce the
endocervical cancers that are missed by current screening, as well as
the \>90% caused by HPV-16 and -18. Those who survive cervical cancer
often cannot have children thereafter. It is so disturbing to see these
cases, knowing that the field is so close to eliminating the disease.
She put the Society of Gynecological Oncologists on record at this
meeting in support of action by federal agencies to approve and license
the vaccine as soon as possible and to disseminate it as broadly as
possible. The SGO supported maximum vaccination of females and, as the
science supports it, of males, and urged the ACIP to recommend that the
VFC program include this vaccine.

Ms. Chris Armenderez, a psychologist from Minnesota, is also a patient
of Dr. Gostout who treated her for invasive cervical cancer. For years,
her Pap test results were returned as Class 2. noting "possible cellular
inflammation," then accelerated to Class 3+. After a miscarriage that
occurred about six month before her diagnosis, she had fairly constant
bleeding, including after sex. An endometrial biopsy found severely
abnormal cells and she had a D&C, after which her cancer was diagnosed.
Before her surgery, she sat up all night holding her sleeping 3-year old
son, mourning that if she died early, he would not remember her. Her
surgery was successful. She stressed the tragedy that women without
access to medical care die of this, and supported implementation of the
vaccine so that no one else would have to go through her experience.

Dr. Carolyn Runowicz, President of the American Cancer Society, also
strongly supported the ACIP's approval of HPV vaccine. Not only is it
historic as the first cancer vaccine, but it can help address cancer's
disparity, which disproportionately affects the underserved, uninsured,
underscreened, and racial and ethnic minorities. If this vaccine is
widely implemented throughout the school system as other vaccines are,
that disparity can be affected for cervical cancer. The vaccine offers
the power and the opportunity to prevent this disease.

Ms. Amelia Toper, a survivor of cervical cancer, urged the ACIP to make
the vaccine available to all individuals, with no age limit. She is a
nurse and married with two children, one 18. Although she always
followed health guidelines such as annual Pap screening, her cancer was
diagnosed in stage 1B. It was removed, but she still worries about
recurrence and for her daughter. That angers her, because this is a
preventable disease. Despite her post-operative discomfort, she drove 1½
hours to urge the vaccine's recommendation by ACIP. She attended to
speak, to protect her daughter and other women. An ACIP recommendation
will extend HPV vaccine's availability to all women and every child,
male and female.

Ms. Susan Crosby is the President and Executive Director of Women in
Government. A national, nonpartisan organization for female state
legislators, the WIG works with the legislators to provide information
helpful to making difficult policy issues. In 2004, 44 states developed
cervical cancer prevention legislation. To date, 37 have passed it, to
learn its causes, incidence, mortality, and what each state can do to
eliminate cervical cancer. She asked the ACIP to help these women
legislators by recommending that the vaccine be made available to all,
regardless of their socioeconomic status.

Ms. Moira Gaul, a policy analyst for the Family Research Council,
welcomed the vaccine's potential for improving health and preventing
deaths. She thanked Merck and GSK for meeting with the FRC to explain
their goals for marketing this vaccine. The FRC will follow the
vaccine's experience to see if it is safe and effective for all, and has
found that to be very encouraging so far. The FRC also will follow the
activities of the pharmaceutical companies, the federal and state
governments, and the medical community as the vaccines are released,
especially to determine if there is any impact on sexual activity. They
are very concerned that information be distributed to public health,
physicians and parents, that HPV will not prevent other STDs, even other
HPV types that cause cancer. Recognizing the recent epidemiological
studies' finding that the vaccine is most effective at earlier ages, she
cautioned the health care community to clearly convey that only
abstaining from sexual contact protects from STDs. But since HPV also
can come from sexual abuse/assault, or marrying someone infected, the
vaccine is a benefit. Since parents should decide about matters of their
children's health, the FRC strongly opposed any mandate, including
school entry, since HPV is not easily transmitted. Health care providers
should discuss the full range of issues affecting health. Counseling on
risk elimination strategies to prevent STDs should be developed, to
match the risk elimination messages for tobacco, drug and alcohol abuse.
The best primary prevention is to limit sexual activity to a single,
life-long monogamous relationship, thereby avoiding the physical and
psychological effects of STDs.

**ROTAVIRUS VACCINE**

***Data Review, Rotavirus Efficacy and Safety Trial (REST)***

Presenter: Dr. Penny Heaton, Merck

> Overview: Overview of Phase III clinical trial study design; safety
> and efficacy data supporting licensure of Merck's pentavalent human
> bovine reassortant rotavirus vaccine (PRV).

The FDA approved the safety and efficacy data of Merck's Phase III trial
of a pentavalent human bovine reassortant rotavirus vaccine (PRV) and
licensed it on February 3, 2006. PRV is an orally administered vaccine
that is suspended in a liquid buffer stabilizer. The buffer protects the
vaccine from gastric acid and the stabilizer allows refrigerated storage
with a 24-month shelf life. It is easily administered directly from the
tube to the infant, and has a three-dose regimen compatible with the
childhood schedule. The trials administered the first dose at age 6-12
weeks, followed by two more doses at 1-2 month intervals on the 2, 4,
6-month schedule and the 2-, 3-, 4-month schedule. The formulation
contains five human bovine reassortants, including the human G1, G2, G3,
G4, and P1(8), which constitute \>90% of the rotavirus strains in the
U.S. and worldwide, and bovine G6 and P7.

The PRV development program was outlined, from the vaccine technology's
licensure in the early 1990s through three Phase II studies and three
Phase III studies: efficacy and safety trial (006), dose-confirmation
efficacy study (007), and lot consistency study (009).

*Evaluations.* The *efficacy* evaluated in the Phase III studies were VE
to prevent rotavirus acute gastroenteritis caused by the vaccine
serotypes (G1-4; non-G1-4 strains containing P1; and VE to reduce
healthcare encounters for rotavirus gastroenteritis, including
hospitalizations, emergency department (ED) visits, and physician office
visits. Other than vaccine *immunogenicity*, the study explored antibody
responses to concomitantly administered other licensed vaccines, and
*safety* relative to serious adverse events (AE), including
intussusception. Other AEs of special clinical interest (for any live
rotavirus vaccine) were fever, vomiting, and diarrhea.

*Study design.* The Phase III trials involved 71,799 subjects, 36,000 of
whom received PRV and 35,799 received a placebo. The age at first dose
was 6-12 weeks and the next two doses were administered every 4-10
weeks, year-round. Case definitions were developed that included ELISA
confirmation for rotavirus gastroenteritis and radiographic, surgical,
or autopsy diagnosis for intussusception. Active surveillance followed
every infant for safety and healthcare encounters for rotavirus
gastroenteritis. The parents were called at weeks 1, 2, and 6 after
vaccination and then every six weeks thereafter, up to a year after
enrollment. Extra calls were made every two weeks during rotavirus
season, and children vaccinated during the season were followed through
that and the next full rotavirus season.

*Vaccine efficacy results.* VE against G1-4 rotavirus gastroenteritis
was:

-   73.8% against any rotavirus disease, 98% against severe disease.

-   Reduction in hospitalizations: 95.8%; in ED visits, 93.7%, in office
    visits, 86%.

-   VE ranged from 68-82% with overlapping confidence intervals, and did
    not vary according to infant feeding status (i.e., breast fed,
    breast and formula fed, etc.)

-   VE in premature infants (N=2000) of gestational age ranging from
    30-35 weeks was similar to that of the overall population, at 70%
    against any severity of rotavirus gastroenteritis.

*Immunogenicit*y. The statistical criterion for demonstrating
non-inferiority for concomitantly administered DT, IPV, Hib, and Hep B
was ≤10 percentage points decrease among PRV versus placebo recipients,
for the proportion who achieve seroprotection (95% CI). The criterion
for pertussis and pneumococcus: ≤2-fold decrease among PRV versus
placebo recipients for the ratio of GMT (95% CI). The analysis compared
antibody responses to the licensed vaccines co-administered with PRV
versus given with placebo, for:

1.  Three doses of DTaP and pneumococcal conjugate vaccine, measuring
    GMTs \~1 month after the third dose (at age \~7-8 months)

2.  Two doses of COMVAX® (Hib/Hep B) and IPV, measuring GMT at \~5 to 6
    months of age.

*Results.* The statistical criteria for diphtheria, tetanus, IPV, Hib,
hep B, and the pneumococcal conjugate serotypes were met. For pertussis,
the statistical criteria for toxoid and FHA were met, but not for
pertactin. No cause for that was found. Retesting mirrored the original
results, but for additional tested subjects and the combined sample, the
criteria for all three compartments were met. There still is no
explanation for the initial pertactin failure, but the reanalysis showed
that the pre-immunization titers were not a factor.

*Conclusions.* The data support concomitant administration of PRV with
the already-licensed childhood vaccines. The clinical significance of
the original lower pertactin titers remains unclear. Additional testing
and/or another study to confirm the reanalysis' favorable results is
being considered. Data show that two-component vaccines, particularly in
post licensure effectiveness studies, show protection against pertussis
that is similar to that of multi-component vaccines.

*Safety results for intussusception.* In all, REST had 35
investigator-diagnosed cases of intussusception. Two cases were
negatively adjudicated and one case could not be adjudicated due to
malfunctioning equipment; all were in the placebo group. Thirty-two
cases were positively adjudicated; of those, four cases occurred after
the child completed the study and again, they were all in the placebo
group. Of 28 cases identified in the year follow-up after a dose, 11
occurred with 42 days of the dose, six in the vaccine group and five in
the placebo group. Seventeen cases, seven in the vaccine group and ten
in the placebo group, occurred outside of that 42-day period but within
the one-year safety follow up.

Intussusception case intervals were charted by dose and by day
post-dose. The relative risk for dose one was 0.9; that for the 42-day
period after any dose was 1.2 (1.6 if adjusted for multiplicity, in a
95% CI of 0.3 to 5.0). The data charted by day showed a sporadic
distribution of the cases. There was no clustering of vaccine cases
without a similar cluster of placebo cases, and none occurred in the
two-week period after Dose 1, the period of greatest intussusception
risk with Merck's former rotavirus vaccine, RotaShield.®

*AEs of special interest.* Fever after each of the three doses was
similar in both the vaccine and placebo groups. For vomiting and
diarrhea, the small differences between vaccine and placebo groups were
small (1.3%) but statistically significant. However, the vast majority
of these cases were characterized as mild by the physician.

*Conclusion*. PRV is efficacious against rotavirus gastroenteritis of
any severity and highly efficacious against severe disease. It reduced
healthcare encounters for rotavirus gastroenteritis by 96% for
hospitalizations, 93% for ED visits, and 86% for physician office
visits. Concomitant use data indicate the PRV can be co-administered
with DTaP, IPV, Hib, hep B, and pneumococcal conjugate vaccine. PRV is
well tolerated with respect to all adverse experiences, including
intussusception with some mild, small increases in mild diarrhea and
vomiting.

***Review of Cost Effectiveness Data***

Presenter: Dr. Mark Widdowson, National Center for Infectious Diseases
(NCID)

> Overview: Updated, expanded results of the cost-effectiveness analysis
> presented to ACIP in October 2005.

This cost effective analysis was done with a probabilistic model in
which a fictitious 100,000 children were followed from birth to age 59
months to estimate the cumulative number of different rotavirus disease
outcomes in that period. The same number of outcomes were calculated for
this cohort, but vaccinated, at 2, 4, and 6 months. Medical and
nonmedical costs of each outcome type were estimated, including the cost
of the vaccine program and adverse reactions. The cost effective ratio
was calculated from the healthcare-payer perspective (medical costs) and
the societal perspective (both medical and nonmedical costs), for cases
averted and life-years saved. The resulting distributions for each input
to the model were then combined to an output distribution, and all
distributions were plotted for a median and a 95th percentile.

*Disease burden* inputs assumed at least one episode of clinical
rotavirus disease per child by age 59 months, among 75% of the U.S.
children (3 million). NCHS provided data on rotavirus-caused diarrhea
outcomes which required healthcare over a ten-year period. That was
multiplied by a published fraction for rotavirus, to arrive at the
annual number of rotavirus disease outcomes per year. Published RV
mortality data were used to calculate annual rotavirus deaths.

*Rotavirus outcomes* ranged from death, hospitalization, hospital
outpatient, ED and physician office visits, and care at home, for \>3
million cases of rotavirus. The large (5 million enrollees) MarketScan
database supplied data for four years of *medical costs*, which were
translated to 2004 dollars and then discounted by 3% for the social and
healthcare perspectives. The median cost calculated for hospitalization
(median of 2 days), for example, was \$2962, ranging from \$1181 at the
5^th^ percentile to \$7426 at the 95^th^ percentile.

*Nonmedical costs* included days lost from work to care for a sick child
(\$118/day), travel for health care, extra diapers, special food, child
care costs, and for mortality, lifetime productivity lost. The data used
for *vaccine efficacy* outcomes (the same five listed above for
rotavirus outcome) were adapted from the Rotateq*®* trial, published in
the January *New England Journal.* This trial used a range of efficacy
measures, from 65 % for mild diarrhea to 90% against hospitalization and
death*.*

The cost effective ratio was calculated for several program costs: dose
of oral RV vaccine, its administration, hospitalization for
intussusception (1:50,000 vaccinees, which added 10 cents to the total
vaccination cost per child), and outpatient workup for
non-intussusception adverse events (an extra 15 cents per child
vaccinated). In the absence of a vaccine price, a cost range of
\$10-\$80 was used, plus \$10 per dose to administer it, resulting in a
range of \$30-\$240 per child.

*Analysis results* for cost effective ratios per case of rotavirus
averted were charted, from the healthcare perspective and the societal
perspective. From the healthcare perspective, the breakeven point was a
total cost of \$33/dose; anything less would be cost saving. From
\$33-\$66, the vaccine program probably would be cost effective; from
\$66-\$143, cost effectiveness would be unlikely, and above \$143, it
would not be cost effective. If administration costs are removed, the
\$66 to vaccinate becomes \~\$12/dose. With Merck's \$62.50 published
list price for the new rotavirus vaccine translating to a total cost per
vaccinee of \~\$217, the rotavirus vaccine would not be cost effective
from a healthcare perspective.

From the societal perspective, breakeven cost is \$107 total cost per
dose. From \$107 to \$156, the program would likely be cost saving, but
unlikely to be so from \$156 to \$238; and after \$238, it would not be
cost saving. The total \$107 cost translates to \$42 per dose, which
again makes Merck's \$62.50 price unlikely to be cost saving from a
societal perspective. But there was also a 20% chance that it may be
cost saving at \$62.50/dose.

Charted by life-year saved, the breakeven points mirror those for each
case averted. But the rarity of deaths prevented by rotavirus
vaccination makes the potential costs per life-year saved much greater,
at \$400,000 per life-year saved versus \$400 per case averted. A
separate sensitivity analysis was done to account for 50% of days lost
from work, subtracting that from the base-case estimate. Increasing the
days off work made the vaccine program more cost effective and
conversely, less cost effective with less days off work. The breakeven
point, including extra days off work, was \$52 per dose, still outside
the Merck price.

The cost effective ratios for different outcomes at \$62.50/dose were
charted from the healthcare perspective: \$470,729 per life-year saved
and \$336 per case averted. From a societal perspective, it would
\$197,190 per life-year saved and \$138 per case averted. Results of a
sensitivity analysis of the model's inputs were charted, showing the
most important to be the cost per hospitalization and per ED visit.

Reduced morbidity in the U.S. due to a vaccine program for the 4 million
birth cohort (July 2004) was charted, assuming 70% coverage for the full
three doses by age 6 months, and 25% coverage for only one or two doses
(half the efficacy). The program would reduce events (hospitalizations,
home care, ED/office visits, etc.) by an average of 51%. There would be
more reduction of hospitalizations and ED visits than of home care
needed, because of the increased efficacy for more severe outcomes. From
the medical perspective, at Merck's price, the program's medical costs
would be \$514 million. But it also would save a substantial nonmedical
cost total of \$300 million, meaning a final cost from the societal
perspective of only \$250 million at \$62.50 per dose and the same
coverage rates.

It is important to remember that vaccines are not necessarily cost
saving. A chart demonstrated that the newer vaccines are less cost
effective than the older ones. One dose of varicella and the hepatitis B
vaccine provide savings, while pneumococcal, meningococcal, pertussis
and rotavirus vaccines incur net costs, from both a case saved and QALY
saved perspective.

Among the analysis's limitations were that the vaccine's true cost will
probably be less than \$62.50 for the VFC program, and that private
contracts introduce another variable. Initial coverage levels also will
likely be much lower thank 70%, which is the DTaP level. While that
would not affect the cost effective ratio, it would affect the overall
net cost of savings of a vaccine program. Finally, the analysis does not
include the psychological costs of anxiety about a sick child or about
adverse reactions.

***Physician/Provider Surveys on Rotavirus Vaccine Use***

Presenter: Dr. Alison Kempe, University of Colorado

> Overview: Rapid turnaround national survey done by CDC of
> practitioners' attitudes and beliefs about rotavirus vaccine use.

This national survey sought to determine pediatricians' knowledge and
attitudes about rotavirus disease, their intentions about recommending a
new rotavirus vaccine, and perceived barriers to rotavirus vaccination.

*Survey methods* were outlined. It was conducted in a sentinel physician
network that was randomly recruited from AAP membership, but designed to
be representative of the AAP membership overall and of the region of the
country, practice location (urban, inner city or not; suburban, or
rural), and setting (private, managed care, hospital-based, etc.) A
panel of pediatricians developed the survey, which was administered by
mail or e-mail in January and February 2006. It is still not completed.

*Preliminary results.* The response rate at the time of the interim
analysis was 66%. Respondents and nonrespondents were similar in terms
of region, practice setting or location; 55% were male, 45% female; 65%
of respondents had \>50% of their patients who were insured; 78% percent
participated in the VFC program.

-   Perceived rotavirus burden: 1) Most common cause of infectious
    diarrhea in children aged \<2 years: 55% strongly agreed; 30%
    somewhat agreed; 2) most frequent cause of severe diarrheal disease
    in children aged \<2 years: 82% strongly agreed; 3) need for a safe
    and effective rotavirus vaccine in the U.S., 51% strongly agreed,
    37% somewhat agreed.

-   Experience with RotaShield:® All the respondents were aware of the
    problems associated with RotaShield® before its withdrawal from the
    market, by: 1) administration: 53% administered it routinely; 9%
    intermittently; 38% had not administered it; 3) experience of
    intussusception: 12% had patients or knew of patients who had
    intussusception suspected of an association with RotaShield.® 4)
    plans to discuss the RotaShield®-intussusception association with
    patients when discussing the new vaccine: 50% would routinely
    discuss it; 32% would do so only if it was raised by the parents; 6%
    would not discuss it; 11% were unsure.

-   Intentions to recommend the new vaccine if ACIP and AAP recommend it
    for routine versus permissive use: 1) Routine use: 50% would
    strongly recommend it; 34% would recommend; 11% would inform but not
    recommend; 1% would recommend against it. 2) Permissive use: 33%
    would strongly recommend, 43% would recommend but not strongly, 19%
    would inform but not recommend, and 1% would recommend against.

-   Speed to implement vaccine use if ACIP/AAP recommended routine use:
    51% would begin within six months of the recommendation; 28%, 6-12
    months; 7%, 1-2 years; 1%, 2 years. Another 14% were unsure.

-   Reasons to wait \>6 months: 1) insurance coverage: 90%; ensure no
    vaccine side effects: 81%; adequate vaccine supplies: 65%; see if
    other providers use the vaccine: 36%; see if parents accept the
    vaccine: 20%.

-   Barriers to giving rotavirus vaccine: 1) failure of some insurance
    companies to cover vaccination: definitely, 51%; somewhat of a
    barrier, 28%; 2) lack of adequate reimbursement for vaccination:
    definitely a barrier, 42%; somewhat a barrier, 32%; 3) parents\'
    reluctance due to RotaShield® withdrawal: definitely a barrier, 30%;
    somewhat a barrier, 42%.

-   Physicians' concerns about rotavirus vaccine safety: 1) definitely a
    barrier, 21%; somewhat a barrier, 26%; 2) upfront vaccine purchase
    costs to the practice: definitely a barrier, 21%, somewhat a
    barrier, 27%; 3) concern about obtaining adequate supplies:
    definitely a barrier: 20%, somewhat a barrier, 33%.

-   Definite barriers to rotavirus vaccination by ≤15% of respondents:
    parental concern about vaccine safety in general, 15%; parents
    thinking rotavirus vaccine is unnecessary, 12%; respondent concerns
    about adding another vaccine to an overloaded vaccine schedule, 9%;
    respondents\' belief that rotavirus was not a severe disease
    requiring vaccination, 5%; time needed to discuss vaccine safety
    with parents, 4%; general administrative burden to the practice, 3%.

The survey data's limitations include potential selection bias, despite
efforts to build a study population representative of the AAP or the
AMA, and that the survey measures the intent to vaccinate rather than
what physicians are actually going to do.

*Conclusion.* Most pediatricians (88%) surveyed believed there was a
need for a rotavirus vaccine in the U.S. If a new rotavirus vaccine were
recommended for routine use, 83% would recommend it, 50% of them
strongly. With permissive use, fewer would recommend ─ 77% overall and
33% strongly. A majority, 51%, would begin using vaccine within six
months of ACIP/AAP recommendations. Barriers anticipated by respondents
included the lack of broad coverage by insurance companies, lack of
adequate reimbursement to physicians giving this vaccine, and parental
reluctance to vaccinate because of withdrawal of the prior rotavirus
vaccine. When discussing new rotavirus vaccine with parents, many would
discuss the association with prior vaccine and intussusception, either
routinely or if it was raised up by the parents.

***Post-licensure Surveillance Plans***

Presenter: Dr. Penina Haber, Office of the Chief Science Officer, CDC

The main tools for post-licensure safety monitoring are the Vaccine
Adverse Event Reporting System (VAERS), a national passive surveillance
system for reporting vaccine adverse events, and the Vaccine Safety
Datalink (VSD), a collaboration between CDC and eight large U.S. health
maintenance organizations with an annual enrolled birth cohort of
\>90,000.

VAERS is a voluntary nationwide reporting system able to detect
previously unrecognized or rare reactions. Monitoring for those will be
done by CDC and FDA, reviewing daily reports and alerts of all serious
adverse events and other medically important conditions. The VAERS main
focus in this case will be on intussusception and suspected
intussusception, any reports of which will prompt immediate follow-up,
and other serious gastrointestinal outcomes. A VAERS analysis of serious
reports includes radiology, surgery, or autopsy information and medical
records confirmation. The Brighton case definition for intussusception
will be applied to verify suspected reports. The reports will be graded
and then compared to the background rates obtained from the VSD data.

The VSD's advantages for vaccine safety research are its access to a
large and well-defined population, with computerized linkable
administrative databases to support controlled population-based studies.
The VSD rapid-cycle (real-time) analysis for Rotateq will monitor for
possible increased risk of intussusception, and evaluate other
prespecified conditions and associations identified from VAERS and from
the manufacturer's Phase IV studies.

The post-licensure study will include infants aged 0-12 months who
received the Rotateq® vaccine, followed for 40 days after vaccination.
Automated outcomes data and chart validation will be in the analysis,
and sequential statistical testing will compare rates of intussusception
and other conditions seen after Rotateq,® to expected rates.

***Merck's Pos-tlicensure Monitoring Plans***

Presenter: Dr. Chris Mast, Merck

Merck is implementing a three-phase or three-component plan for
comprehensive pharmacovigilance to monitor vaccine safety: 1)
maintenance of a large safety database of ongoing and future clinical
studies of Rotateq® among \>71,000 subjects, to monitor the safety of
this product; 2) two pharmacovigilance activities, one a prospective
population-based study assessing intussusception and general Rotateq®
safety, and the other enhanced passive reporting through telephone
follow-up of all intussusception cases and expedited case reporting to
the FDA. FDA also will be apprised of all adverse events monthly, in
addition to Merck's quarterly reporting. And, 3) Merck will coordinate
and collaborate with CDC and the FDA on these respective
pharmacovigilance activities.

Merck's active surveillance plans, approved by the FDA, were summarized.
The prospective surveillance study will explore both intussusception and
general safety in the same study population. The study population is a
large insured population, separate and complementary to the CDC/VSD
study. In that, Merck will evaluate all infants (\~44,000) receiving
Rotateq® (on- or off-label) during the study period. Safety will be
assessed for 30 days after each dose, as well as alternate intervals for
the secondary analysis.

The post-licensure study will compare the incidence of intussusception
among vaccinees to the background rate. The latter will be examined in a
baseline study before licensure, to confirm the study's operating
statistical assumptions. A sequential design similar to Dr. Haber's
description will assess intussusception cases as they occur and
continuously monitor during the study period. One objective to be
explored is the use of unvaccinated concurrent controls if potential
confounding factors can be controlled.

Safety will be assessed descriptively by recording adverse experiences
among infants who received Rotateq® in periods after vaccination.
Analytical assessment of general short-term vaccine safety will compare
post-Rotateq® vaccination adverse events with two control periods. In
one, vaccinees will be their own control group, and the other is a
historical cohort. All adverse events resulting in hospitalization or ED
visits during the study period will be captured. This method has been
used for other vaccines, and the results were published.

*Discussion* included:

-   Dr. Lieu raised the cost effective analysis results of \$178,000 per
    life year saved, and \$138 per case averted. Another analysis that
    would be helpful, would be to go on to calculate dollars per QALY.
    She had quickly calculated a net societal cost, after deducting work
    loss, of \~\$250 million per year and 1.5 million cases averted. She
    calculated further that if about a day of life is traded to avoid a
    case of rotavirus, that the vaccine would appear cost effective at
    \$50,000 per QALY saved. Dr. Widdowson reported a life year saved
    analysis as briefly discussed but not done, because the relatively
    brief rotavirus episodes would not greatly affect the subsequent
    QALYs. However, that could be estimated.

-   Dr. Campbell asked what the duration of the vomiting or diarrhea was
    among the 15%-25% of vaccine recipients, so as to understand the
    impact on parents' time lost from work. Dr. Heaton responded that
    these episodes, being described as mild, would typically only last
    1-2 days.

-   Dr. Kempe conveyed Merck's own surprise that the physicians asked
    about Rotateq were so generally positive, although they tend to be
    so about new vaccines in general. They seemed to view Rotateq as a
    new vaccine

-   Dr. Morse asked if parents had been surveyed as well, and if so, if
    they shared the pediatricians' concerns about safety. Dr. Jim
    Alexander, of NIP's health communications staff, reported that CDC
    is doing key informant interviews and focus groups of parents,
    especially young parents likely to have, or about to have young
    children, to assess their attitudes about new vaccines.

    ***Rotavirus Vaccine Working Group Draft Proposed Recommendations***

Presenter: Dr. Umesh Parashar, NCID

The recommendation options for vaccine use in general were for routine
or universal use, permissive, or a targeted strategy to high-risk
groups. Considerations discussed by the Working Group included:

-   Burden of rotavirus illness in the U.S. in children aged ≤5 years,
    \~70% (2.7 million) children will have an episode of rotavirus
    gastroenteritis, resulting in \>200,000 ED visits, \>400,000
    outpatient visits, 55,000-70,000 hospitalizations, and 20-60 deaths
    annually. Charted cumulative hospitalization rates showed 90% due to
    rotavirus by age 2 years.

-   High-risk groups for severe RV disease include infants with low
    birth weight, those born to young mothers, and those socially
    disadvantaged. But these groups comprise only a fraction of overall
    severe RV cases, so a targeted vaccination strategy would not
    effectively reduce severe rotavirus disease. Routine or universal
    immunization of infants with three doses of this vaccine given at 2,
    4, and 6 months of age was chosen as the optimum strategy. Dose 1
    would be given from 6-12 weeks of age, as done in the clinical
    trial. That is supported by available safety data. All three
    vaccinations should be done by 32 weeks of age, with at least a 4-10
    week interval between doses.

-   NIS data show an 88% uptake of the first DTP dose by 12 weeks of
    age, then rising in a slow plateau to 98% by age one. So, although
    having the strict cutoff for 6-12 weeks of age would potentially
    reduce vaccine coverage by 10%, the Working Group opted to follow
    the age period supported by safety data from the clinical trial, at
    least in the initial years of the immunization program until more
    data are available through post marketing surveillance.

-   The vaccine can be administered to infants with transient mild
    illnesses and can be co-administered with other vaccines given at 2,
    4, 6 months of age.

-   There are two contraindications proposed by the working group: T- or
    B-cell deficiency (including infants of HIV-positive mothers, unless
    the infant is clearly uninfected), since this is a live viral
    vaccine. The second is serious allergy to any vaccine component or
    to a previous dose of the vaccine.

-   Precautions are stated for infants with moderate or severe acute
    gastroenteritis at the time of vaccination and infants with moderate
    or severe febrile illness. In both cases, vaccination should be
    delayed to recovery, unless the pediatrician fears that the child
    will not return for vaccination. Infants with pre-existing chronic
    gastrointestinal disease can be vaccinated, since the risks of the
    disease are greater. There is no association of this vaccine to
    intussusception, but infants who have had a prior episode of
    intussusception should not receive this vaccine. Premature infants
    can be immunized if they are at least six weeks of age, clinically
    stable, and are being or have been discharged from the hospital
    nursery. Infants who have recently received any antibody-containing
    blood products may be vaccinated.

-   The small risk of shedding and transmission (after dose 1, by
    12%-13%) does not outweigh the risk of transmission from a child
    with wild rotavirus disease to household contacts, so the infant
    should be vaccinated. Vaccine should not be readministered to
    infants who regurgitate a vaccine dose. Limited related safety and
    efficacy data indicated that, since the vaccine has a high titer,
    even a partial dose might lead to some immune response and
    protection.

*Discussion*:

-   Dr. Abramson understood the data-based rationale for the very tight
    vaccination schedule, but strongly advised that very clear guidance
    be provided on it, as children will certainly be presented for
    vaccination both early and late. Dr. Treanor said that guidance for
    vaccinating outside the window will be developed.

-   Dr. Halsey urged a more permissive recommendation for HIV-positive
    children. Antiviral therapies have greatly reduced maternal
    transmission of HIV (to only 5%), and immunosuppression is minimal
    hivHIVuntil months after birth. Making HIV status a contraindication
    will discourage needed studies from being done.

-   Dr. Poland suggested that the broader definition of altered
    immunocompetence in the General Recommendations be applied, and also
    edited the "theoretical benefits" phrase to be "known benefits
    outweigh theoretical risks."

-   Dr. Heaton clarified that the REST design selected the early 6-12
    week window because the intussusception rate is low at that time,
    which helped them to ensure that any repeated signal of
    intussusception risk would be detected. Merck has no concern about
    vaccinating at an older age. A first dose at 13 weeks will still be
    clinically acceptable. The post-licensure studies will look
    specifically at age issues and at vaccinating HIV-positive children.
    They do not expect the latter to be problematic since this group has
    received live OPV with very few adverse events.

-   Dr. Phil LaRussa, of Columbia University, clarified that most
    HIV-exposed children will have had two negative postnatal tests, one
    at age ≥2 months, and almost all remain negative to 18 months of
    age.

-   Dr. Deborah Wexler commented on this recommendation's precaution for
    moderate to severe "febrile" illness, which differs from other
    recommendations in citing "febrile." She favored consistency unless
    there is a reason to specify fever.

-   Dr. Heaton said that the clinical trial exclusions may not have been
    sufficient to prevent trial participation by a child with an
    unrecognized IgA deficiency. And, in terms of shed disease, children
    with natural disease shed ten- or eleven-fold more virus from
    natural infection than they do from a vaccine dose.

**Dr. Allos moved to accept the proposed recommendations, for a
universal recommendation at 2, 4, 6 months, with the minor changes
suggested**, and Dr. Stinchfield seconded the motion.**.**

*Further discussion* included agreement that the HIV qualification would
be changed from a contraindication to a precaution and that the
recommendation would say the vaccine "should be administered between
6-12 weeks of age."

**Vote**

**Conflict:** Drs. Treanor, Poland

**In favor:** Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu,
Marcuse, Morse, Morita, Stinchfield, Womeodu, Abramson

**Opposed:** None

**Abstentions:** Treanor, Poland

**The motion passed.**

***VFC Resolution***

Presenter: Dr. Greg Wallace, NIP

With the ACIP's approved of a general universal recommendation for the
rotavirus vaccine, a vote was now needed to incorporated the vaccine
into the VFC program. This was done in two parts; to add the rotavirus
vaccine to the VFC's list of covered vaccines (to now total 15
vaccines), and then to specify its administration, details of which were
lifted directly from the recommendations:

-   Administer dose one from age 6-12 weeks, with the routine dosage at
    2, 4, and 6 months, with 4-10 week intervals between each dose, and
    none given past age 32 weeks.

-   The standard language about referring to the package insert about
    dosages was included, as well as that on serious allergic reactions.

-   Language on altered immunocompetence was moved to the Precautions
    section, including that on HIV and other conditions related to
    immunocompetence.

-   \"Febrile\" was deleted from the language on moderate to severe
    illness.

-   Provider judgment was advised for children with pre-existing chronic
    GI conditions.

-   The intussusception experience of the previous rotavirus vaccine was
    acknowledged and this vaccine was expected to be helpful for
    children who have had intussusception. Studies to date were
    described.

*Discussion* included:

-   Dr. Pickering expressed concern about moving all immunodeficient
    diseases to the Precautions section, since that would include rare
    primary immune deficiencies (e.g., T- and B-cell deficiencies,
    x-linked gamma globulinemia) for which this live vaccine should not
    be given. However, Dr. Paul Offit commented that although those
    children can shed virus for long periods, they tend to get mild
    disease. Even children with severe combined immunodeficiency suffer
    little from natural infection, and he doubted the vaccine would be
    of greater risk. He would delay the vaccine only if the child was
    about to have immunosuppressive therapy such as a bone marrow
    transplant, and even then the child's age and whether it was
    rotavirus season would be factors in the decision.

-   Ms. Stinchfield pointed out that HIV had already been moved to the
    Precautions section, not the other primary immune deficiencies. She
    suggested strengthening the language on altered immunocompetence in
    the Contraindications section to specify "known T- and B-cell
    immunodeficiency," to protect physicians who may not know by 12
    weeks that a child has an immunodeficiency. Dr. Abramson agreed.

-   Dr. Halsey addressed the complexity of this question. The AAP has
    loosened its strictures on giving live vaccines to immune deficient
    infants. They now provide some flexibility for vaccinating children
    with conditions such as B-cell immune deficiency disorders, those
    receiving replacement immunoglobulin, or those with IgA deficiency.
    There just should be consultation with an immunologist or infectious
    disease person to evaluate each situation.

-   Mr. Kevin Malone, of the Office of General Counsel, confirmed that
    the VFC language had to be specific before a vote could be taken.

-   Dr. Sam Katz objected to singling out HIV, as there is no evidence
    that rotavirus poses an undue burden to HIV-positive children. In
    the U.S., children born to an HIV-positive mother will be seen by
    someone, but that is not the case in Africa, and listing HIV as a
    contraindication to this vaccine will severely affect them.

-   Dr. Baylor pointed out that the vaccine label's precautions include
    infants with primary acquired immunodeficiencies, including
    HIV/AIDS.

-   Ms. Stinchfield noted that live vaccines such as varicella are given
    to children with HIV who have a normal CD4 count, and questioned why
    this live vaccine should be treated any differently than others.

-   The language advising against administration after 32 weeks would be
    changed to "should be given by 32 weeks."

Dr. Pickering regretted that the complexity of the immunology made this
decision difficult. Of the four major types of deficiency (T-cell,
B-cell, phagocytic, and complement), live viral vaccines can be given to
children with the last two, so grouping all four as contraindications is
incorrect. But on the other hand, splitting them might make the
recommendation too complicated for what is trying to be achieved in a
small number of children.

Dr. Wallace agreed to edit the recommendation based on these comments,
particularly in the Precaution section to advise seeking the advice of a
specialist. With that, and language on altered dosage intervals, he
would return for the ACIP's vote in the morning.

**ACIP GENERAL RECOMMENDATIONS ON IMMUNIZATION**

***Revisions to the General Recommendations***

Presenter: Dr. Ed Marcuse, General Recommendations Working Group Chair

Overview: Past and new changes to the ACIP General Recommendations
document

The ACIP General Recommendations document is its compendium of the
information needed about immunization. Its revision every \~5 years is
always a challenge, given the rapidity of change (or persisting lack of
data) in the field. This revision is expected to be released in
September, pending the ACIP's approval on this day, perhaps with
additional edits.

General recommendation changes previously presented to the ACIP were:

Vaccine administration:

-   A 5/8" needle is adequate for intramuscular injection; the reference
    was removed to the 7/8" needle, which is no longer produced.

-   There is no need to aspirate prior to vaccine injection

-   There is no preferred site for intramuscular injection, but a
    cautious preference is expressed for the thigh in infants and the
    deltoid in adolescents and adults.

Storage and handling of immunobiologics:

-   The language was strengthened to advise keeping vaccine properly
    stored to the expiration date (to stop automatic discard of vials
    opened \>30 days).

-   The recommendation was strengthened to contact the state health
    department on the procedure for mishandled or inappropriately stored
    vaccines. This is controversial, since there are no clear data to
    guide this decision, and it depends on the vaccine and how it was
    mishandled. Since expert guidance is needed, the Working Group felt
    the health department was the first place to check.

Altered immunocompetence:

-   A permissive recommendation for the use of varicella and
    pneumococcal conjugate vaccine after hematopoietic stem cell
    transplantation in immunocompromised patients was inserted, with a
    reference.

-   A caution was inserted about the use of live vaccines in patients on
    tumor necrosis factor, alpha inhibitors and other isoantibodies,
    after related advice from experts that these are analogous to the
    effect of high dose steroids.

*Discussion* included:

-   Dr. Hull asked rhetorically how a state health department could be
    expected advise on complex issues like vaccine mishandling if the
    ACIP cannot. He asked if the NIP could develop a table or formal
    guideline to help advise this field. Dr. Kroger reported that the
    revised recommendations will have a table of information for a range
    of vaccines derived from the respected *Vaccines* by Plotkin and
    Orenstein. But realistically, most questions are case-based,
    frustrating any kind of standard reply. Contacting the manufacturer
    could be the best suggestion. Dr. Kuter reported that Merck has some
    algorithms potentially helpful to answer the questions of vaccine
    appropriateness for use.

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-   State representatives emphatically agreed that guidance is
    desperately needed. Dr. Kelly Moore, Medical Director of the
    Tennessee Health Department, developed her state's guidance herself,
    based on the WHO and Australian guidelines. Ms. Beth Rowe-West, who
    manages the North Carolina state program, reported requests for
    judgments at every site visit. NIP cannot be called for guidance
    about every refrigerator that is too warm or cold, something they
    hear about "at least twice a day."

-   There was some opinion that mis-stored vaccine simply should not be
    administered, to protect the integrity of vaccines as a whole. But
    Dr. Abramson raised the problem posed when the mishandling is
    realized in retrospect. Dr. Moore agreed, reporting common
    experiences of practitioners who found their vaccine frozen and had
    to contact thousands of families thereafter. The final decision is
    made by an adequately informed parent who can require the physician
    to revaccinate. But, just as fever will not be found without taking
    a temperature, such incidents will not be known unless someone looks
    at the temperature logs.

-   Dr. Salisbury reported the U.K.'s similar experience. The instances
    of the recommendation being ignored over time, however, are far less
    than those of a cleaning person who forgot to re-plug the
    refrigerator on Friday evening. Calling the manufacturers rarely
    helps, as they generally just advise consulting the package insert,
    being loathe to risk the liability of any other decision. In his
    opinion, people just need to make sensible judgments; if the vaccine
    was not out of the cold chain long, it is a reasonable risk to use
    it. It is easier to discard it, but that could be just an expensive
    waste.

-   Ms. Lynn Bahta, of Minnesota's health department, disliked the
    removal of the previous recommendation's text of what to do if a
    child receives what turns out to be a nonviable vaccine. That
    removal leaves no national standard at all on which to rely.

Dr. Abramson recommended that this be discussed further in a conference
call. He asked those with comments or concerns to email him or Dr.
Marcuse about this issue and the changes outlined, which will be
addressed again in June.

***New Revisions to the General Recommendations since October 2005***

Presenter: Dr. Andrew Kroger, NIP

The entire 2002 General Recommendations document was not revised, but
significant new changes were made. These have been reviewed by the ACIP
liaisons and the Association of Immunization Managers. Most of the major
changes came from the ACIP statements revised in the past four years.
These include:

-   Timing/spacing of newly licensed vaccines.

    -   Live vaccines/LAIV: Parenterally administered live vaccines must
        be deferred after receipt of blood products (and vice versa).
        The deferral period can range from 2 weeks to 11 months,
        depending on which product was given first. This interval is
        necessary because blood products can interfere with replication
        of parenteral live vaccines. . There are no data on this, but
        subject matter experts' opinion (CDC, Influenza Branch) is that
        the antibody response to LAIV will not be affected by
        circulating antibody, making unnecessary the interval between
        administration of LAIV and antibody-containing blood products.
        The new language reads: "Yellow fever, oral Ty21a typhoid
        vaccine, and live attenuated influenza vaccine are exceptions to
        these recommendations."

    -   A 28-day interval between LAIV and other live vaccines not given
        simultaneously was recommended by ACIP in 2005.

    -   The AAP currently recommends a one -month interval between Tdap
        and MCV4 not given simultaneously. The new language recommends
        "No interval between LAIV and antibody containing blood
        products;" a "four week interval between nasal or injected live
        vaccines if non-simultaneous," and a "1 month interval between
        Tdap and MCV4 if non-simultaneous."

-   Contraindications and precautions: New vaccines were added to the
    table: Tdap, TIV, LAIV, MCV4, and MPSV, and their
    contraindications/precautions were taken from the published
    vaccine-specific recommendations. There are provisional
    recommendations for Tdap, listing severe allergic reaction and
    encephalopathy as contraindications. Precautions are: moderate or
    severe acute illness, GBS, progressive neurologic disorder until the
    condition is stabilized, and a history of Arthus reaction, causing
    severe local reactions. For the latter, Tdap vaccination is deferred
    unless it has been ten years since the previous dose.

-   Vaccine administration:

    -   Tables were added for the new vaccines' (Tdap, MCV4, MPSV)
        recommended dose and route. This will include the issue of
        IM-recommended vaccines given subcutaneously (e.g.,
        meningococcal conjugate vaccine). A suggestion to include
        combination vaccines will be added, but had not been
        incorporated when this draft was distributed.

    -   A table addresses needle length by age (0-10 and ≥11 years),
        body mass, and site, as regards intramuscular injections.
        Different factors determining appropriate needle length for each
        group are addressed. It calls for the use of at least a 1"
        needle length for all preadolescents, adolescent, and adults.
        But that also depends on body mass; if low, there is a risk of
        hitting bone. This needs to be addressed in more detail.

    -   A table on the treatment of anaphylaxis addresses only the IM
        and oral treatment regimen, for both pediatric and adult
        patients.

-   Altered Immunocompetence. A new table presents the recommendations
    for vaccination of persons with altered immunocompetence that were
    presented to the ACIP in October 2005. The table is organized by
    disease categories parallel to those in the AAP's 2006 Red Book
    (i.e., primary-secondary conditions also classified by cell-type,
    such as B- or T-cell deficiencies). The column for \"Recommended
    Vaccines\" may be relabeled "Risk-Specific Recommendations By Virtue
    of Altered Immunocompetence" to avoid the perception that only the
    listed vaccines should be used for that specific disease. The last
    column addresses vaccine efficacy and adds comments.

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-   Special Situations:

    -   LAIV and Protein and Protein-Derivative vaccines reactivity. MMR
        and varicella not administered concurrently to a tuberculin skin
        test can cause a false negative result. The current (2002)
        recommendation is, when the vaccine is given first, to delay the
        PPD/TST for at least four weeks post-vaccination. For LAIV, a
        live vaccine whose effect on the PPD/TST is unknown, the
        Influenza Branch subject matter experts recommended treating
        LAIV like other live virus vaccines, spacing the PPD/TST four
        weeks later if it is not simultaneous, or performing the PPD/TST
        first.

    -   Severe allergy to vaccine components. The new language clarifies
        that the preservative thimerosal in vaccines given to children
        has only been in trace amounts, or not at all, since mid-2001.
        It also provides the new recommendations for the inactivated
        influenza vaccine licensed in 2005 for children.

    -   Vaccination of internationally-adopted children. In view of the
        new hepatitis B recommendations, the language for international
        adoptees now recommends both a surface antigen test and
        vaccination as primary approaches. With varicella vaccine
        recommendations, the definition of "immunity" will be taken from
        the varicella-vaccine-specific provisional recommendations.

Dr. Kroger asked for the ACIP's approval of these revised
recommendations subject to the inclusion of actions at this meeting and
minor revisions of language, format and citations.

*Discussion* included:

-   Dr. Hull strongly recommended revision to the statement indicating
    that since mid-2001, vaccines routinely recommended for infants and
    have been manufactured without thimerosal. Taken out of context,
    that sentence has been used to resist state legislation to restrict
    the use of thimerosal in vaccines. He agreed to provide replacement
    text.

-   Dr. Poland reported being asked about the intradermal vaccinia
    (smallpox) vaccine, and recommended including that as well. It was
    not included because it is not a universally recommended vaccine.
    However, it could be appropriately included to meet the needs of
    such broader use of these recommendations as by the military.

-   Dr. Stan Gall asked about the simultaneous administration, in the
    postpartum period, for RhoGAM, MMR and varicella. Dr. Kroger
    responded that the 2002 guidance was not changed in its direction to
    give MMR after RhoGAM to protect against rubella. He agreed to check
    the vaccine-specific recommendations on varicella since it is being
    encouraged for postpartum use and, as Dr. Gall noted, there are a
    fair number of women who need RhoGAM at that time.

-   Dr. Jeff Duchin suggested adding to the international adoptee text a
    recommendation that family members ensure they are up to date on
    their own vaccinations.

-   Dr. Doug Campos-Outcalt, of the AAFP, asked why the hepatitis B
    surface antigen recommendation did not include surface antibody
    inhibition. Dr. Kroger answered that the hepatitis B
    vaccine-specific recommendations advise use of the surface antigen
    test for large groups of people considered at high risk, in order to
    identify carriers. The "large group" includes international adoptees
    from high-risk countries, so to simplify matters, it was decided to
    recommend the test for all international adoptees. It was also felt
    that in view of the lack of records, providing the one dose to all
    also was advisable. Dr. Abramson commented that a positive surface
    antibody test would establish the need for vaccination and would be
    a cost effective way to proceed. Dr. Wexler said that the presence
    of antibody could be maternal in origin, and not vaccine. For that
    reason, the child should receive three doses of vaccine unless they
    have a document recording those doses. But the surface antigen test
    must be done to identify a carrier. Dr. Kroger added that the
    vaccine might, although rarely, produce a positive surface antigen
    test. A footnote may be inserted to advise serology first, then
    vaccination.

-   Dr. Schaffner questioned the necessity of the statement about
    "potential interference between LAIV and other live attenuated viral
    vaccines,\" since LAIV replicates only in the upper airway while the
    other vaccines are administered parenterally and replicate
    systemically. Dr. Kroger responded that the new language reassures
    that there is no concern about LAIV relative to circulating antibody
    in blood products, nor about LAIV simultaneously administered with
    another live vaccine. But it does advise the interval when LAIV is
    not administered simultaneously with another live vaccine. But Dr.
    Marcuse raised Dr. Schaffner's question again, noting that the ACIP
    to date has not considered if there should be any spacing for the
    LAIV or rotavirus live vaccines. He asked if a nonspecific immune
    response from a parenteral vaccine could prevent a topical vaccine's
    take, or vice versa. Dr. Plotkin answered that interference could
    occur for two reasons: the introduction of interferon, which could
    be tested, and an effect on cellular immune response, primarily CD4.
    Relevant data from the manufacturers on these questions would be
    good to have. Dr. Jeff Stoddard, of MedImmune, stated that there are
    not yet any data from the ongoing immunogenicity studies to answer
    that question, but that would be available soon. In that event, Dr.
    Marcuse asked if the rule of spacing should be continued until more
    data are in hand. There were nods all around to that question,
    indicating agreement.

    **Public Comment**

Mr. Gary Stein, of Families Fighting Flu, related that his daughter
Jessica had died of influenza. People always think that "it can't happen
to us." That is not true, but individuals can make a difference. For
those reasons, he attended to encourage ACIP to recommend annual
influenza vaccination for all children. On the next day, ACIP was to
discuss including children aged 2-6 in the universal vaccination
recommendation. He urged the committee to pass that vote to expand this
recommendation. It would be a step in right direction, since many
pediatricians do not recommend influenza vaccination now, and ACIP
expansion of the recommendation will spur them to do so. He asked that
the ACIP act to spare another family the tragedy of losing another
child.

Mr. Joe Lastinger, who lost his daughter Emily to influenza, was joined
by Richard and Luisa Kanowitz and John Bellovich, who also had lost
their children to flu. He called ACIP's recommendation critically
important. Had it been in place several years ago, Emily might have been
vaccinated and she would be alive today. He understood the concern about
the vaccine supply, but he had researched what is available. His
impression was, if children to age 6 are included, that would add 20
million children to the population for vaccination. CDC's data indicate
that 40% of those are already covered due to their health status or that
of a household contact, so in reality, only \~12 million more children
would need to be covered. And of those, it is likely that many would not
seek the vaccine. Even in his own community, people who knew Emily and
what had happened to her still do not vaccinate their children. If only
75% do, that would be an additional 9 million children. The
manufacturers expect to produce 120 million doses for the next season.
He asked the committee to please consider the millions of children who,
based on its decision tomorrow, could be vaccinated next year and saved,
or not. If the members are uncertain, he asked them to please think
about these particular children, and the hundreds of others who might
still be alive today had they been vaccinated.

With no further comment, the meeting adjourned at 6:03 p.m. and
reconvened at 8:00 a.m. on the following morning.

**FEBRUARY 22, 2006**

**CDC DIRECTOR'S COMMENTS**

Presenter: Dr. Julie M. Gerberding, CDC Director

CDC remains committed to the basic public health issues affecting
Americans' daily lives: obesity; chronic diseases such as cancer and
cardiovascular disease; tobacco use, injuries, and disabilities. But
media attention goes to special issues such as terrorism and pandemics,
also necessary work, which challenges CDC's ability to keep its
portfolio balanced.

An outline was provided of the CDC programs funded by its current \$8
billion appropriation, according to program increases, stable funding
and decreases. Funding has increased (1600%) since 2001 to build and
maintain the Strategic National Stockpile and to respond to terrorism,
supported the Vaccines for Children program and work on birth defects
global immunization and environmental health.

However, the increase for immunization, when adjusted to the price index
(an accounting method for the cost of science), is actually stable
funding. While that is something to be grateful for, with increasing
numbers of new vaccines and the growth of adult and adolescent
vaccination programs, strategies realigning resources or reconfiguring
programs will be needed to meet Congress' deficit-reduction budget
trends. Additionally, the benefit to other programs, such as the
President\'s proposed budget's inclusion of \$93 million for domestic
HIV/AIDS testing, is offset by no funding for the public health work
that naturally follows testing, such as partner tracing and treatment.

CDC received \$3.1 billion of an emergency \$7.1 billion supplemental
appropriation for influenza pandemic preparedness and response. This
will also benefit seasonal influenza response, improving seasonal
vaccine supply and development of new antiviral drugs; and it has
already improved CDC's rapid alert communications capacity.

These are all part of CDC's strategy to maximize and extend the benefit
from categorical investments to much broader applications, by
concertedly directing budget resource decisions to support very specific
health impact goals. Concurrent stressing of efficiencies in-house has
produced a focused, lean and effective structure that earned CDC the
OMB's commendation for appropriate resource utilization. These two
approaches are being generalized broadly across CDC. Dr. Gerberding
thanked the committee, not only for its very hard work to support
immunization, but also for wise counsel on such resource allocation
issues.

But other programs have lost ground in funding, including occupational
safety, injury prevention, TB, STDs, public health research, leadership
and management initiatives, business services support, buildings and
facilities, and the youth media campaign. Immunization also still faces
considerable challenges. More vaccines mean more doses to more people in
more age groups and communities. This accelerates the increasingly
complex process of delivering them to those most in need, monitoring and
evaluating immunization safety, and scaling up all this to match
production scale, while maintaining the program's overall credibility
and vaccines' safety.

But the challenges fade in the light of such rewarding inaugurations, as
addressed at this meeting, of another cancer defeated by vaccine (HPV),
and the immense impact the rotavirus vaccine will have to save children
lives worldwide.

*Discussion* included:

-   *Vaccine distribution*. A vaccine summit held recently examined
    seasonal influenza vaccine production and distribution options to
    close the supply/demand gaps. Production will rise to at least 100
    million doses of seasonal vaccine, and the market will be driven to
    create that demand. The problem with vaccine distribution is that
    CDC does not own the vaccine. Further adjustment with the private
    sector's distribution system is needed. Last year, it was the
    smaller purchasers who did not receive vaccine, in part due to
    Chiron's delayed product release or their own late order. CDC's VFC
    purchase also commands a lot of the initial supply. One strategy is
    the join small purchasers into groups to gain more clout. Another is
    production modernization, but that may take 3-5 years.

-   *Vaccine financing systems*. Multiple and perhaps combined solutions
    will be needed to address the many components of vaccine financing.
    Only one aspect is risk versus profit (e.g., the egg-based influenza
    vaccine process, and Viagra versus other therapeutic vaccines).
    Government purchases also help to ensure a reliable market.

-   Dr. Abramson noted ACIP's mandate to examine the safety/efficacy and
    cost effectiveness of vaccine, but not the funding implications.
    There is concern about the possibility substantial social inequity
    that could result from unequal access to the new vaccines. Dr.
    Gerberding acknowledged that many public health investments, as a
    matter of policy, have to balance the potential benefits. She hoped
    to hear more of these concerns and potential resolutions. Dr. Gellin
    reported that the National Vaccine Advisory Committee (NVAC) has
    begun to address those issues, which differ from the ACIP's mandate,
    and they also increase focus on vaccine financing.

-   *CDC reorganization.* Dr. Schuchat reported that the Coordinating
    Center for Infectious Diseases holds three CDC infectious disease
    centers: the NIP, NCID and NCHSTP. But over the next month, the NIP
    will transition into a larger activity tentatively being called the
    National Center for Immunization and Respiratory Diseases, to link
    vaccine-related work from the laboratory bench through vaccine
    delivery and immunization services, including influenza activities.

    **OLD BUSINESS**

    ***Resolution to Add Rotavirus Vaccine to the VFC***

Presenter: Dr. Greg Wallace, NIP

Dr. Wallace presented the revised resolution, which incorporated the
edits from the previous day. It specified that dose one should be
initiated for infants aged 6-12 weeks and notes that the last dose
should be administered by 32 weeks of age.

Two options were offered to address altered immune status, which was
formerly a contraindication to vaccination. This could be moved this to
the Precautions section, advising the physician to consider the
potential risks and benefits for infants with, for example, lymphoma and
other immunocompromised conditions. And, severe immunodeficiency such as
severe antibody deficiency or severe combined immunodeficiency could be
cited under Contraindications.

*Discussion* included the implications to Medicaid payment if a child
aged \>32 weeks receives a third rotavirus dose at an office visit. The
committee was reminded that the VFC not a reimbursement program; it only
provides vaccine to VFC providers. The members were advised to simply
recommend on the technical issues. The resolution clearly states that if
eligible, the child should receive the vaccine. Any impact on VFC
program would have to be addressed by the Office of General Counsel. The
VFC auditors will note vaccine administered outside of the recommended
time frame, but are unlikely to penalize the practice. Dr. Marcuse asked
if the footnote on this could simply be removed from the resolution. But
Dr. Seward recommended retaining the age recommendation, given the
removal of the "should not be" wording, reassurance that VFC children
will be covered at \>32 weeks, and that the new wording is consistent
with the package insert and ACIP recommendations (which will be
revised). Ms. Lynn Bahta agreed, adding that the footnote is instructive
to the practitioner.

Dr. Marcuse **moved to accept resolution as presented, but to remove the
footnote on the dosing interval.** Dr. Morse seconded the motion.

**Vote**

**In favor:** Marcuse, Poland

**Opposed:** Beck, Campbell, Finger, Gilsdorf, Lieu, Morita, Treanor,
Womedou, Abramson

**The motion failed.**

Dr. Finger **moved to accept the resolution as presented with
grammatical corrections.** Ms. Stinchfield seconded the motion.

**Vote**

**In favor:** Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu,
Marcuse, Morita, Poland, Stinchfield, Treanor, Womedou, Abramson

**Opposed:** None

**Abstained:** None.

**The motion passed.**

*Additional comment.* Dr. Mark Feinberg, of Merck, requested an edit for
clarification and completeness. Rather than, as now stated, referring to
the vaccine's safety when administered after 12 weeks of age, as based
on data from the clinical trial, he suggested text to say \"safety or
efficacy of the vaccine administered, the first dose administered after
12 weeks of age.\" However, since this was suggested after the vote, it
was not incorporated into the VFC resolution.

*Vaccine Storage**. ***Dr. Abramson reported a decision by NIP to meet
with the Association for Immunization Managers to discuss possible
solutions to the issue of improperly stored vaccine, to help refinement
of the ACIP wording. They will discuss what additional information might
be available (e.g., from the Australian guidelines or the
manufacturers), and potentially needed educational initiatives and
research.

***Changes to the ACIP General Recommendation***

Presenter***:*** Dr. Andrew Kroger, NIP

*Needle length.* The wording was revised as suggested on the previous
day. The Working Group will continue to discuss table revisions for
intramuscular (IM) injection based on age, body mass, and site, to
provide all the data sources. **The ACIP accepted this as presented.**

*Severe allergy to a vaccine component* (i.e., influenza
vaccine/thimerosal). With inactivated influenza now the standard
recommendation for children, new language was needed:

\"Since 2001, inactivated influenza vaccine is the only vaccine
routinely recommended for children under two years of age that contains
thimerosal as a preservative. Inactivated influenza vaccine also may
contain trace amounts of thimerosal that are residual from the
manufacturing process. A thimerosal-free formulation of inactivated
influenza vaccine for use in children was licensed in 2005. TT, Td, and
DT vaccines contain thimerosal as a preservative."

Matters remaining to be discussed were the necessity of a spacing
interval with non-simultaneous administration of LAIV and other live
vaccines, and RhoGAM immune globulin and varicella; the issues
(including cost effectiveness) related to repeated vaccination for
international adoptees with unknown hepatitis status, including the
conduct of a hepatitis B surface antigen test and a hepatitis B surface
antibody test. Language will be added to address vaccination of family
members of international adoptees.

*Discussion* included:

-   Dr. Hull suggested just having the table say that vaccines may
    contain preservatives to maintain their potency and safety, then
    listing those that might have preservative. There was **general
    agreement** to that recommendation

-   Mr. Phil Hosbach, of SanofiPasteur, reported that Tt and Td also are
    available with only trace amounts of thimerosal.

-   Dr. Baylor asked that the FDA Website be referenced, which will also
    be useful with new vaccines released in future.

*Altered Immunocompetence*

Dr. Katz asked a question in reference to the changes needed to Table
11, specifically relabeling of "Recommended Vaccines" column to clarify
the vaccines recommended for people with altered immunocompetence. Dr.
Abramson clarified, on Dr. Katz' question, that Table 11 would be
modified. There may be other edits, but neither Table 11's nor any
others were expected to be substantive.

Ms. Stinchfield **moved to approve the ACIP General Recommendations with
the modifications presented**. Dr. Poland seconded the motion

**Vote**

**In favor:** Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu,
Marcuse, Morita, Poland, Stinchfield, Treanor, Womedou, Abramson

**Opposed:** None

**Abstained:** None.

**The motion passed unanimously.**

**VARICELLA ZOSTER IMMUNE GLOBULIN**

***VZIG Update: Availability of a New Product***

Presenter: Dr. Mona Marin, NIP

In 2004, the only U.S.-licensed manufacturer of varicella zoster immune
globulin (VZIG) announced their withdrawal from the market. CDC's
literature search on possible VZIG alternatives was presented to the
Varicella Working Group and, in October 2004, ACIP recommended the use
of intravenous immune globulin (IGIV). However, VZIG was preferred for
post-exposure prophylaxis of patients at high risk of complications and
severe disease. The VZIG supply was expected to last to April, 2006, but
will probably be exhausted by March 1.

By July 2005, CDC, FDA and subject matter experts decided that, in view
of weak scientific data supporting an alternative method, FDA should
encourage new IND applications for immune globulin. Given the impending
depletion of VZIG supply, FDA made an IND, Varizig®, available in
February under an expanded access protocol. Varizig® is manufactured by
Cangene Corporation, Canada. It is a lyophilized, purified human immune
globulin preparation made from plasma, with high levels of antivaricella
antibodies, immune globulin Class G. When reconstituted, is provides a
\~5% IgG solution for IM administration. As an IND, administration
requires informed consent.

The Varizig® indication is for patients exposed to varicella, who have
no immunity from natural disease or age-appropriate vaccination, and who
are at high risk for severe disease and complications. These are the
same patient groups who would receive VZIG: those who are
immunocompromised; pregnant women; neonates whose mothers developed
varicella symptoms from \<5 days before delivery to two days after;
premature infants of \>20 weeks gestation who are exposed as neonates
and who have varicella naïve mothers; and those \<28 weeks\' gestation
or who weigh ≤1,000 grams at birth and who are exposed as neonates,
regardless of maternal varicella history.

Providers should make every effort to obtain and administer Varizig*®*
to these groups as soon as possible after exposure, and it can be
administered as late as 96 hours; it. When that cannot be done, one dose
of IGIV can be used as an alternative, at a recommended dose of 400
mg/kg. That is also true for pregnant women, or the physician may choose
to closely monitor her for varicella symptoms and begin acyclovir
treatment if illness develops. The vaccine comes in 125-unit vials. The
recommended dose is 125 units per 10 kilograms of body weight up to a
maximum of 625 units (five vials); the minimum dose is half a vial, 62.5
units for patients weighing \<5 kilograms. Standard varicella
vaccination should follow Varizig® in the absence of any
contraindications, but only after an interval of five months after
Varizig®. The vaccine is unnecessary if the patient develops varicella
after receiving Varizig.®

FFF Enterprises distributes Varizig*®* under the expanded access
protocol. It has received central IRB approval; local IRB approval is
not required, but they should be informed of the protocol. If they
reject the central IRB's jurisdiction, the Varizig® can still be shipped
but the local IRB must supervise its administration. In an emergency,
Varizig® can be used once without regard to IRB review requirements, to
ensure the patient is promptly treated. But that must be reported to the
IRB within five working days and the IRB must review any subsequent
Varizig® treatment.

Interested pharmacies and healthcare providers can fill out the FFF
forms in advance to be prequalified to receive and use Varizig®. When
needed, the completed release can be faxed to FFF, which determines
patient eligibility and assigns a patient number to those eligible. Or,
FFF can provided the product release form upon request to its 800
number, fax or e-mail it back and begin the process. Generally, Varizig®
can be provided within 24 hours. This information will be published in
the *MMWR.*

*Discussion* included a report that, aside from the *MMWR* notice,
Varizig's® availability will be published in medical journals, and
promoted at the conferences held nationwide by the Department of
Education and Communication. Details can also be received from FFF. The
*MMWR* will also be circulated to professional associations and the ACIP
liaisons, and the ACIP members also were encouraged to promote it within
their own fields. There is a link to FFF's standard two-page request
form on the FDA Website as well. This presentation's slides and all
others presented at this meeting were to be posted on CDC's Website
within a week.

**INFLUENZA VACCINE**

***Introduction***

Presenter: Dr. Ban Allos, Influenza Working Group Chair

The Influenza Working Group has met monthly, and on occasion bimonthly,
to discuss vaccine composition changes for the 2006-2007 season; to
develop a recommendation on the use of adamantanes (as \>90% of the
strains are resistant to them this season); to develop a suggested ACIP
recommendation related to vaccine tiering, and to suggest an ACIP
encouragement to vaccinate children aged 24-59 months this year, that
would be expanded to an recommendation the following year.

The working group also discussed the rationale for extending influenza
vaccination recommendations to persons at risk for nonhuman influenza
(e.g., those working with animals, poultry, or swine and travelers to
areas affected by avian flu) as a way to prevent reassortment; this plan
was ultimately not adopted by the group. Finally, a universal influenza
vaccination policy may eventually be recommended after the working group
reviews the existing data and data gaps.

To date, the vaccine's safety, ability to prevent hospitalizations and
deaths, feasibility, and economic aspects have influenced expansion
recommendations. The working group acknowledged that the proposed
expansion of recommendations for influenza vaccination to include
children aged 24 through 59 months of age represented a paradigm shift
\-- one based on prevention of outpatient, ED and pediatrician visits.
Future changes to the recommendations may consider the indirect effects
of vaccination and prevention of the theoretical risk of reassortment.

***Review of 2005 Influenza Vaccine Summit Meeting.***

Presenter: Dr. L.J. Tan, AMA

> Overview: Activities and recommendations of the 2005 Influenza Vaccine
> Summit

Dr. Tan outlined the content of the Influenza Summit referenced by Dr.
Gerberding, which was held January 24-25. The Summit's presentations and
complete minutes are on the Web site
[www.ama-assn.org/go/influenzasummit](http://www.ama-assn.org/go/influenzasummit).
These summits have been cosponsored by AMA and CDC since 2001 to address
influenza vaccine supply issues.

The January meeting involved 112 organizational stakeholders in the
pubic/private partnerships related to influenza vaccination (e.g.,
manufacturers, distributors, professional medical association,
pharmacists, health insurance, etc.) Its objectives were to identify
vaccine supply, ordering, and distribution issues in the last influenza
season; to review any trends revealed by survey data; to develop
recommendations on those issues; and, to develop subsequent activities.
Among the issues identified were:

-   Vaccine supply and distribution. Summit recommendations included:
    ensure timely information regarding vaccine distribution and supply
    that is effectively communicated to providers, public, and the
    media, by all stakeholders in influenza immunization; ensure a
    transparent vaccine-distribution system that is seen as equitable,
    with clear, timely, and frequent communication to providers about
    vaccine ordering and shipment policies; and encourage optimal
    vaccine usage to avoid vaccine disposal at season's end (e.g.,
    no-return policies; government purchase; tax credits for returned
    vaccine). The many partners of the Summit supported preseason
    stockpiles for CDC from multiple manufacturing sources to buffer the
    effect of a manufacturer's production failure

-   CDC tiering recommendations. The summit wrote a letter to ACIP
    noting that while the recommendations are national, vaccine supply
    issues are regional, due to regional implementation. The Summit
    recommends that tiering should only be used when there are issues of
    vaccine supply and if implemented, a standard but flexible plan
    should be created for such implementation. Tiering implementation
    must be consistent across all providers and its removal should
    depend on regional-level vaccine supplies.

-   The vaccine testing and release process needs to be as efficient as
    possible to help resolve long-term vaccine supply.

-   Recommendations to reinvigorate demand included moving toward
    universal immunization and encouraging research on related data gaps
    (e.g., research relevant to school-age children aged 6-19). This
    issue is considered by the Summit as critical to long term stability
    of influenza vaccine supplies and to reaching the Healthy People
    2010 immunization-related goals.

-   The impact of vaccine shortages on the performance measurement of
    institutions (e.g., hospitals, long-term care facilities) has to be
    acknowledged. If vaccine is unavailable, institutions should not be
    held to those performance standards.

-   Influenza vaccine tracing is needed at all levels, as is a clear
    definition of the related federal, state, and local government roles
    in obtaining and distributing vaccine. Legislation to ban
    thimerosal-containing influenza vaccines and all
    thimerosal-containing vaccines is being advanced to the state level
    and the Summit urges that partners become involved in legislator
    education on the science of the issue.

-   Improve vaccine demand, especially for the predicted \>100 million
    doses anticipated for the 2006-2007 season. Educate and target high
    priority populations better; target education on vaccine's cost
    effectiveness to third-party payers and employers; extend the
    immunization season; plan for when there is excess vaccine; and, as
    discussed on the previous day by Families Fighting Flu, give
    influenza disease a "face."

-   The manufacturers should limit partial shipments, especially if
    there is no shortage. Any partial-shipment policy should be
    consistent and well communicated to providers. Pre-booking and
    distribution data for influenza vaccine should be available at least
    to public health. The providers without vaccine should be identified
    at the beginning of the season, to ensure that they get vaccine if
    there are any supply gaps.

-   Vaccinate healthcare workers.

*Summit accomplishments* included:

-   Establishment of a vaccine-supply task force to address supply and
    distribution challenges; the letter to ACIP discussing the
    inadequacy of the tiering system; expressing support for universal
    influenza immunization recommendations; and, urging ACIP to promote
    vaccine use in a timely and clear manner.

-   The Summit Communications Working Group and its Executive Committee
    have begun examining short-, mid-, and long-term vaccine
    communication needs. A Reimbursement Working Group is analyzing
    influenza vaccine coverage from the perspective of third-party
    payers.

-   A statement will be issued on the importance of establishing a
    national adult immunization program.

-   The summit is working with CDC, manufacturers, distributors, and
    partners to identify the data available to better track vaccine and
    determine how it could be accessed.

-   FDA and the manufacturers are being urged to study how vaccine
    production can be optimized.

The summit is interested in leading development of a partnership to
develop a national, coordinated strategy for seasonal influenza, in
terms of influenza prevention as well as vaccine production and
utilization, to lower its overall morbidity and mortality.

***Presentation by National Foundation for Infectious Diseases***

Presenter: Dr. Carol Baker, President-Elect

> Overview: NFID position on influenza burden on and vaccination need by
> children with asthma.

Despite years of recommendations to vaccinate children with asthma for
influenza yearly, it appears that rates are low (\<40%) given that these
children are not routinely assessed for the need for vaccination against
influenza. Two studies, in a large HMO and an asthma clinic, examined
influenza vaccination in children. The former had 10% coverage; the
latter, 25%.

In response, the NFID convened a roundtable in November of 2005 with
representatives of \~20 major medical and public health groups. After a
full day's discussion of the known data about influenza and its impact
on children with asthma, they arrived at several key messages, which
were published in a *Call to Action* that was available at this meeting.
Its key messages are:

-   Influenza and other respiratory viruses can be deadly for children
    with asthma. Viral respiratory infections precipitate wheezing in
    asthmatic children. Influenza is the only vaccine preventable viral
    respiratory infection. Morbidity is increased in asthmatic children
    with influenza; they receive more antibiotics and are much more
    likely to have an outpatient medical visit.

-   Asthma puts millions of children at increased risk of morbidity and
    mortality. Over 6 million American children have asthma and it is an
    urban epidemic. It is the third leading cause of children's
    hospitalization and precipitates \~750,000 ED visits by in children
    aged \<15 years. In 2002, 170 children \<15 years died of
    asthma-related causes. In the 2003-2004 influenza epidemic, 45% of
    the 153 children and adolescents who died from influenza had asthma.

The NFID call for action invites a comprehensive effort to: 1) increase
influenza vaccination rates, especially for asthmatic children; 2) add
or increase the annual influenza vaccine outreach activities to asthma
education programs and treatment guidelines; 3) support practice-based
efforts; 4) increase local influenza vaccination rates, and 5) use
public health forums to advertise influenza as a vaccine-preventable
disease, and the need of children with asthma for the vaccine's
protection. ACIP's help in this initiative, by strengthening its own
recommendations, will be appreciated by the NFID.

***Update on Influenza Antiviral Resistance***

Presenter: Dr. Alexander Klimov, NCID

> Overview: Recent antiviral resistance and WHO/FDA-recommended
> influenza vaccine composition for the next season

*Adamantanes resistance*. Resistance to adamantanes (amantadine and
rimantadine) can emerge rapidly as a result of a single mutation in the
influenza virus' M2 protein. Over 7,000 human influenza A (H3N2) viruses
isolated worldwide were tested at CDC in 2005. An alarming increase in
the proportion of viruses resistant to adamantanes was observed in
several Asian countries. In previous seasons, the proportion of
resistant A/H3 viruses circulating in the U.S. has increased from \~1%
(1994-2004) to 12% in 2005.

Recently, more than 200 Type A isolates collected in the U.S. from
October through December 2005 were tested at the Influenza Branch, CDC.
Most of the tested viruses were of the H3N2 subtype and few were of H1N1
subtype. Of the influenza A(H3N2) isolates, 92.3% had the Ser-31-Asn
amino acid change in the M2 protein and were amantadanes-resistant. The
proportion of resistance among few H1N1 isolates was found to be 25%.

CDC published a health alert on January 14, 2006*,* and recommended
against the use of amantadine and rimantadine for the treatment or
prophylaxis of influenza in the U.S. during the 2005-06 influenza
season. The data about resistance of currently circulating viruses to
adamantanes were published in the *MMWR* (dispatch) on January 17, 2006
(vol 55, pp. 1-2) and in JAMA on February 1, 2006 (*JAMA*,
2006;295:891-894).

*Vaccine composition for next season*. Data collected by WHO
collaborating center laboratories (including one at the Influenza
Branch) were charted. Influenza A (H1N1) comprised 19% of the
circulating strains, mostly in Asia and Africa. Influenza A (H3N2)
isolates comprised 45% of the strains, predominating in North America,
followed by Asia, Africa and Europe. B/Victoria-like viruses held 27% of
the share, with Africa leading, followed by fairly even rates in Europe
and North America and some in Asia. B/Yamagata-lineage viruses were the
least seen strains (9%). So, the most common (64%) strains circulating
were of type A, with H3 dominating, followed by influenza B viruses.

A new antigenic variation of H3 was identified. Also, B/Victoria-lineage
viruses became predominant (75%) over B/Yamagata-lineage isolates (25%).

In response, WHO announced on February 15 that the H1 vaccine component
would be the same: A/New Caledonia/20/99(H1N1)-like virus. The H3
vaccine component was replaced by A/Wisconsin/67/2005 (H3N2)-like
viruses (recommended strains for vaccine production are
A/Wisconsin/67/2005 and A/Hiroshoma/52/2005). B/Victoria-lineage
strains, B/Malaysia/2506/2004 and a B/Malaysia-like virus --
B/Ohio/1/2005 -- were recommended as the type B component of the
vaccine. FDA's Vaccines and Related Biological Product Advisory
Committee (VRBPAC) agreed with the WHO recommendations.

***Influenza Surveillance Data Update***

Presenter: Dr. Katherine A. Poehling, Vanderbilt University

> Overview: Inpatient and outpatient surveillance data from the New
> Vaccine Surveillance Network (NVSN) (2001-2004) and published data.

CDC's NVSN is a population-based, laboratory-confirmed influenza
surveillance network in the counties of Rochester, New York; Cincinnati,
Ohio; and Nashville, Tennessee. The influenza burden among children aged
≤5 years was surveyed among in-patients in three counties over four
influenza seasons, who were admitted for ARI or fever. Out-patient
surveillance was done in the same three counties from 2002-2004. This
was done in the only pediatric ED in the three counties, and in 1-3
outpatient clinics per county. Cases for both groups were confirmed by
PCR or viral cultures.

A preliminary sub-analysis was done of NHIS parental reports nationally,
indicating that 5% of children aged 6-23 months are at high risk, as are
\~10% of children aged \>2 years. For both, the primary high-risk
condition is asthma, which is diagnosed twice as much in children aged
\>2 years than in the younger children (10.6% versus 5.2%,
respectively). The mean rates of lab-confirmed influenza-related
hospitalizations were calculated per 1000 healthy children and then for
low- and high-risk children, for three age groups: 0-5 months, 6-23
months, and 2-5 years of age. The results were as follow.

*Hospitalization rates* are high in children aged 0-23 months, at
4.5/1000, versus 0.9 for 6-23 months (0.65 for low-risk and 5.38 for
high-risk) and 0.3 for age 2-5 years (0.25 and 0.75 for low- and high
risk, respectively). *Conclusion:* Those data support the current
recommendation and, since these rates decrease with age, a universal
recommendation may not be supported.

*Outpatients.* For the 13-week influenza season, outpatient (clinic and
ED) visit rates were calculated using data from the NVSN and the
National Ambulatory Medical Care Survey (NAMCS) and the National
Hospital Medical Care Survey (NHMCS) survey. The rates were similar in
the mild 2002-2003 season. But in 2003-2004, the rates were about three
times higher for the high-risk group, although comparable between all
children and those at low risk. The published Tennessee data of 19
influenza seasons (Neuzil et al, *NEJM* 2000) showed and average of
\~90-100 outpatient visits per 1000 children aged 2-4 years, and
\~80/1000 among those aged 5-9 years. For those children aged ≥2 years,
\~80% were prescribed antibiotics. *Conclusion.* The outpatient data
indicate rates potentially sufficient to encourage or recommend
vaccination of healthy children aged 24-59 months. Other than direct
effects, the expanded vaccination may produce herd effects. Influenza
surveillance should include older children and adults to monitor related
policy effects.

*Discussion* included:

> This preliminary analysis could not explain why a smaller effect
> emerged from high risk conditions among both out- and in-patient
> visits by children aged 2-5 years. It could be that the higher
> vaccination rates being seen include those higher-risk children.
>
> The two B lineages are of different genetic and antigenic groups;
> human serology data on the anti-hemagglutination antibody level of the
> Yamagata lineage indicate a \>50% difference to B Victoria.
>
> Dr. George Peter suggested, as this type of analysis moves to
> older-age groups of children, to consider using the potentially
> sensitive marker of school absenteeism for earlier outbreak detection.
>
> Dr. Nichol complimented Dr. Poehlingh on the data for children age
> \<5. She hoped ACIP would fully recommend vaccination for that age
> group in spring or summer, especially if abundant doses are available.
> She also supported Dr. Baker's suggestion to improve attention to
> children at higher risk. That could be accomplished by enhanced ACIP
> recommendation language, and/or publication of a Notice to Readers in
> the *MMWR.* She added that high risk adults aged \<65, whose
> immunization rates also are low, might be added.
>
> Dr. Lieu agreed and reported a similar cost analysis being done by her
> and Dr. Lisa Prosser to advance vaccination of children aged 2-18
> years. These data will well supplement that work, which suggests that
> universal vaccination would be very cost effective and good policy.
>
> Dr. Tan reported that an AMA task force is examining supply and
> distribution issues for short-term contingencies and to reach the
> long-term goal of increasing demand. From both that analytical
> perspective and philosophically, the AMA supports universal
> immunization recommendations.
>
> Dr. Temte reported analysis of Wisconsin's sentinel surveillance data,
> indicating surprisingly high percentages of children age 0-4 years
> presenting to clinics for ILI. They do not progress to hospitals or
> EDs, but are conveying influenza to all their contacts.

***Key Issues/Changes Proposed for the 2006-07 Influenza
Recommendations***

Presenter: Dr. Nicole Smith, CDC Influenza Branch

The changes proposed for the next season's influenza recommendations
were to:

-   Change the vaccine composition as described, to two new strains for
    the influenza A (H3N2) virus and influenza B vaccine components. The
    influenza A (H1N1) virus component remains unchanged.

-   Recommend against the use of adamantanes this season.

-   Change wording on vaccine tiering to advise against prioritizing
    without a vaccine supply delay or decrease, and to prepare for
    contingencies if a disruption to the vaccine supply occurs.

-   Recommend vaccination to prevent illness among an expanded group of
    young children, encouraging vaccination of children aged 24 through
    59 months of age. The Influenza working group will present data in
    October regarding whether other age groups should be considered for
    inclusion among the groups for whom annual influenza vaccination is
    recommended.

-   Additional edits to these recommendations reiterate the importance
    of two doses for children not vaccinated previously, and emphasize
    that influenza vaccine should be offered throughout the season.
    Other updates on the influenza vaccine products, coverage level
    changes, and references will be included in the revised statement.

Options presented to ACIP for the influenza-related recommendations,
with pros and cons, were:

1.  Continue the current recommendation to annually vaccinate children
    24 through59 months of age with high risk conditions, or if the
    children are household contacts of high risk persons. Change the
    wording on tiering and recommend against the use of adamantanes, and
    the additional edits. *Advantages:* This option is potentially the
    most feasible; it allows for a continued focus on efforts to improve
    the vaccination coverage levels of existing priority groups and it
    provides an opportunity to see if the vaccine supply is stabilized.
    *Disadvantages:* This option continues the risk-based
    recommendations for children aged \>24 months, and it does not take
    advantage of expected increased vaccine supply, which could be used
    to help vaccinate more people, including children 24 through 59
    months of age.

2.  Option 1, plus encourage annual vaccination of children aged 24
    through 59 months beginning in 2006-2007; defer the full
    recommendation until the Working Group presents their analysis in
    October about the potential inclusion of other ages in the
    recommendation. *Advantages:* This option incorporates a broader
    understanding of the true burden of illness; it may help to reduce
    the risk of influenza-related complications for all children aged 24
    through 59 months (not just among those children who have high risk
    conditions); and it gives the vaccine manufactures advance notice of
    the potential need for increased vaccine production in 2007-08,
    while not producing a huge immediate increase in vaccine demand.
    *Disadvantages:* The use of encouragement language presents a
    less-clear recommendation that may confuse parents, providers, and
    payers; the evidence in support of routine vaccination is not as
    strong as for other high risk groups; this approach sets a precedent
    of using ambulatory care visits as a measurement of burden of
    disease; and, if there are vaccine supply delays or interruptions,
    this option could strain the vaccine supply available to reach young
    children.

3.  Option 1, plus recommend annual vaccination of children aged 24
    through59 months of age beginning in 2007-2008. *Advantages*: The
    same advantages as Option 2, except that a recommendation is more
    likely to be implemented and therefore a greater reduction in the
    risk of influenza-related complications for all children 24
    through59 months of age might be expected. *Disadvantages:* Same as
    Option 2.

4.  Option 2, plus encourage routine vaccination of household contacts
    and out-of-home caregivers of children aged 24 through 59 months
    beginning in 2006-2007. *Advantages:* This option should raise the
    awareness of the importance of influenza vaccination and the concept
    of protecting others; it is consistent with other recommendations
    for vaccinating household contacts and caregivers; it takes
    advantage of the expected increase in vaccine supply to reach
    household contacts and caregivers; and it may increase the public's
    demand for influenza vaccine, thereby offering manufacturers an
    incentive to increase their production of influenza vaccine.
    *Disadvantages:* Same as Option 2.

*Discussion*:

-   Mr. Phil Hosbach reported sanofi pasteur's plan to make 50 million
    doses of influenza vaccine which should be enough to cover the extra
    children covered. Sanofi's production also could be increased by 1-2
    million doses if necessary.

-   In response to a question by Dr. Joseph Bresee, of the Influenza
    Branch, all of the ACIP members indicated that they agreed with the
    language on amantadanes and tiering changes.

-   Dr. Gilsdorf asked if 50 million doses would be enough. Dr. Smith
    reported that National Immunization Survey data from the first two
    years of the recommendation encouraging influenza vaccination. The
    proportion of children 6 through 23 months of age who were reported
    as being fully vaccinated against influenza increased from 4.4% in
    2002-03 to only 8% in 2003-04, but children in this age group who
    received one or more doses of influenza vaccine increased from 7.2%
    to 17.5%, respectively. National Immunization Program staff have
    developed preliminary estimates indicating that an additional 5.3
    million healthy, 24-59 month-old children who are not household
    contacts of high risk persons would be covered by the proposed
    change. Behavioral Risk Factor Surveillance System data indicate
    that \~39% of these children would have been previously vaccinated,
    and, therefore would only require one dose of influenza vaccine per
    year (compared to two doses for previously unvaccinated children in
    this age group).

-   There was an inquiry regarding whether vaccinating older children
    could reduce the disease burden in the 0-6 month-old group through
    herd immunity; Dr. Smith was unsure of the data and noted that the
    working group was planning to present a review of the data at the
    October ACIP meeting. In the meantime, Dr. Smith highlighted that
    the ACIP was currently being asked to consider the direct benefits
    of reducing the risk of influenza-related emergency department and
    outpatient visits among children 24 through 59 months of age.

-   Although no formal Vaccines for Children Program (VFC) resolution
    could be voted upon until there is a full ACIP recommendation, a
    permissive VFC resolution would allow the use of influenza vaccine
    for any VFC eligible child, regardless of his/her age. Dr. Wallace
    reminded the committee of the complexities of the influenza
    vaccines' different formulations. SanofiPasteur produces a pediatric
    formulation of the influenza vaccine that is approved for use among
    children 6 through 35 months of age. During the last two years,
    sanofi has not distributed all of its doses of this product. The
    vaccine produced by sanofi for children 3 years of age and older is
    also used by adults and, therefore, there is competition among the
    different age groups for that presentation. The Chiron-produced
    influenza vaccine can be used for children 4 years and older, but
    they have had some production issues during the last two years.
    FluMist, the live attenuated influenza vaccine produced by MedImmune
    can be used for healthy children 5 years and older.

-   Andrew McNight, of GlaxoSmithKline, reported their plan to produce
    20-30 million doses of influenza vaccine for the American market
    this next season (2006-07). The vaccine will be licensed for persons
    ages \>18 years in the U.S., but is licensed abroad for use in
    persons ≥6 years of age. Eventually, GSK expects to produce
    influenza vaccine for the U.S. that will be approved for younger age
    groups.

-   Dr. Poland confessed to being bothered by "creeping incrementalism."
    Bicycle helmets are recommended, knowing there are not enough, as
    are annual mammograms without enough facilities to do them. Already,
    40,000 people die annually of a vaccine-preventable disease. And,
    with the development of resistance to adamantanes, use of antivirals
    for treatment of influenza is less of an option. Health care workers
    are frustrated with the additional groups added every year and the
    "ticking clock" of pandemic influenza threatens co-infection and
    reassortment. Dr. Poland declared that now is the time for ACIP to
    be bold and to recommend influenza vaccination for all Americans;
    the recommendations could be phased in over time. No other strategy
    would so well galvanize all involved, from the manufacturers to
    governments. It would point out the high risk target groups while
    also clearly articulating the vaccine's rationale at the community
    and population levels. He suggested a universal recommendation could
    be phrased as follows: "Annual influenza vaccination is encouraged
    for all Americans to reduce morbidity and mortality, work and school
    place disruption, and infection. It also aids pandemic preparedness,
    phased in over time. There also are specific age and condition
    recommendations for groups who should receive priority for vaccine."

-   Dr. Ben Schwartz, of the National Vaccine Program Office, reported
    on the October 2005 meeting on readiness for a universal influenza
    vaccination recommendation. The attendees agreed t hat there is a
    large burden of illness associated with influenza and that the
    overall effectiveness of influenza vaccine is not optimal and varies
    by season depending upon the circulating strains and vaccine match.
    Workshop participants acknowledged information gaps remain on the
    indirect effects of vaccinating some populations (e.g., incomplete
    data on the benefit of school children to reduce disease among
    family members and the elderly), and on the effectiveness and safety
    of repeated annual vaccinations. For example, some data indicate
    decreasing effectiveness among some children with cystic fibrosis.
    The cost effectiveness of influenza vaccination depends on several
    factors, including vaccine cost and the population being targeted,
    and feasibility was raised by immunization managers. Ultimately, the
    meeting participants reached consensus to move toward a universal
    recommendation, but recommended that implementation occur in stages
    over time to avoid unintended consequences and to have time to fill
    the information gaps.

-   Dr. Jacques Morena, of the Immunization Safety Office, urged that if
    ACIP were to recommended more studies and data to support a
    universal recommendation, it should also recommend the funding to do
    so.

-   Dr. Baker strongly recommended extending the recommended age group
    fro vaccination to 59 months of age (Option 3) and urged ACIP to
    skip encouragement language in favor of a direct recommendation. She
    argued that the option would ensure that influenza vaccination for
    children 24 through 59 months of age would be covered by private
    health plans and VFC, that pediatricians would adopt the practice,
    and that currently unvaccinated asthmatic children would be
    vaccinated along with children. Dr. Neuzil agreed with Dr. Poland,
    with a feasible incremental approach. If monitored with the New
    Vaccine Surveillance Network, the public health infrastructure also
    could be established so that eventually, the effectiveness of the
    influenza vaccination recommendations for older children and adults
    could be evaluated.

-   Dr. Jim Turner, of the American College Health Association, also
    agreed with Dr. Poland's proposal, which Dr. Turner had recommended
    4-5 years ago. He offered another variation on the proposal: rather
    than saying "persons at high risk of complications should consider
    getting the vaccine," just saying "persons should consider..."

-   Dr. Walter Orenstein opposed using the word "encourage," because it
    does not help clinicians dealing with private insurers nor does it
    set a clear standard of care. He advised ACIP to either make a
    recommendation or not, rather than issue an "encouragement," and he
    preferred that the recommendation be issued sooner rather than
    later. Dr. Orenstein pointed out that there already is a permissive
    recommendation to vaccinate the whole population, and 40-50% of the
    2-49 year-old age group is already covered by existing
    recommendations. Whatever is decided, he suggested that the ACIP
    signal that influenza's mortality and morbidity are unacceptable,
    and that strategy changes will periodically be reviewed, right up to
    considering full universal vaccination.

-   Dr. Wexler, of the Immunization Action Coalition, commented that the
    influenza vaccine is already recommended for 66% of the population.
    Since only 90 million doses are used (by half the population), the
    current approach clearly is not working well. Risk-based (e.g., for
    asthmatic children) recommendations are hard to implement and do not
    help families of 11-12 year-old children who die from influenza. She
    advised simply saying "The vaccine can be given to anyone who wants
    it." She suggested that this approach would give health care
    providers the responsibility to offer the vaccine or to tell their
    patients about its availability (rather than having to ask for it),
    as was done for meningococcal vaccine before a full recommendation
    was issued.

-   Ms. Elisa Kanowitz, mother of Amanda, who died March 1, 2004, was
    very encouraged thatACIP was considering expanded recommendations.
    She supported the full recommendation, urging the committee members
    to "avoid analysis paralysis." According to Ms. Kanowitz, the data
    are good, and more children like Amanda, Emily, and Jessica will die
    by next year. With more than enough vaccine next year, it should be
    recommended for the whole population.

-   Dr. Poland asked if the morbidity for the 2-5 year-old group was
    different from that of adult risk groups. Dr. Neuzil noted that Dr.
    Poland was raising an important point that had not been clearly
    addressed. Dr. Neuzil reported that morbidity is measured
    differently among children and adults, but one analysis of
    outpatient visit data found that the results were almost identical
    to age 15, beginning at \>2 years of age. According to Dr. Neuzil,
    the hospitalization data are probably the best proof of the higher
    rate of severe complications associated with influenza among those
    aged \<5 years compared to those aged 5-49. But the rates in those
    aged \<5 is driven a lot by children under 2 years of age.

-   Dr. Poland commented that, if the risk is the same, why parse out
    pieces of it? Dr. Abramson raised the feasibility issue as one
    reason. For example, access to children aged to 5-6 years is pretty
    good, and how to implement the recommendation in stages is part of
    policy considerations.

Dr. Poland offered an Option 5, or Option 3+, to recommend vaccination
for all Americans. Essentially, this proposal was Option 3 to recommend
annual vaccination of children aged 24-59 months, beginning in the
2006-2007 season, and encouraging everyone to get vaccine. "Annual
influenza vaccination is encouraged for all Americans to reduce its
related morbidity and mortality, work and school place disruption, and
infection. It also aids pandemic preparedness, phased in over time.
There also are specific age and condition recommendations. These groups
should receive priority for vaccine."

*Further discussion* occurred which included Dr. Beck\'s clarification
that there were two alternatives on the table, which did not include
full recommendation, but recommended vaccination for those aged 24-59
months and encouraged vaccination for everyone else (i.e., universal),
with the latter phased in. In his opinion, this effort was part of the
strategy to move toward universal vaccination that was not committing
ACIP to a time line, but was providing a goal to move toward.

Dr. Lieu moved to recommend influenza vaccination for children aged
24-59 months, beginning immediately. It was assumed that vaccination of
their household contacts and out-of-home caregivers was also included in
this motion. Dr. Allos seconded the motion. In a friendly amendment,
**Dr. Poland moved an addendum to encourage all to be vaccinated for
influenza as part of a strategy to achieve universal immunization**.
This was seconded by Dr. Allos.

Dr. Gilsdorf asked the state health department representatives how the
proposed recommendation would be received. Dr. Moore, of Tennessee's
health department, asked that the universal implementation be divided
into pieces to avoid exceeding the vaccine supply, having to tier the
recommendations, and struggling to reach the high risk populations. Dr.
Morita agreed; Massachusetts' situation would be the same.

Dr. Lieu reiterated the original motion **to recommend vaccination for
children aged 24-59 months.** No second was required as it had already
been done.

**Vote**

***Recommended influenza vaccination for children aged 24-59 months***

**In favor:** Allos, Beck Campbell, Finger, Gilsdorf, Lieu, Marcuse,
Morita, Poland, Stinchfield, Treanor, Womeodu, Abramson

**Opposed:** None

**Abstained:** None

**The motion passed.**

Dr. Poland **moved to state that annual influenza immunization is
encouraged for all as part of a strategy to achieve universal
immunization.** Again, no second was needed.

*Discussion*:

-   Dr. Lieu supported the sentiment, but found the encouragement
    confusing, and remained concerned that it may disrupt state
    agencies' work.

-   Dr. Treanor was opposed, because it implied that ACIP had made a
    decision for universal vaccination in the absence of a discussion of
    data supporting the proposal, which he felt needed to occur.

-   Dr. Marcuse supported the sentiment, but he was reluctant to use
    "encouraged." To achieve credibility, he wanted the discussion of a
    statement about a universal immunization vision to include vaccine
    efficacy and safety data; provider and consumer education; and, more
    information on efficacy and on herd immunity effects from
    vaccinating preschool versus school-aged children.

-   Ms. Beth Rowe-West, of North Carolina, voiced her own and other
    program managers' familiarity with the use of the word "encouraged"
    by now, and their support of universal vaccination. Dr. Moore, of
    Tennessee's immunization program, also commented that the health
    departments would do less to implement this proposal than the
    private sector. She reported that in Tennessee, the health
    department provides only administers 10% of the influenza
    vaccinations; the private sector gives 90%.

Dr. Tan stated the AMA's support of the language proposed. But to move
the discussion along, he suggested, rather than saying \"as part of an
evolving strategy to move towards universal vaccination,\" saying \"as
part of an evaluation of a universal immunization strategy.\" He noted
that his suggestion would loosen the language somewhat, but still allow
encouragement of annual influenza immunization for all. Dr. Poland
accepted that amendment and seconded it.

Further discussion noted that the concept of moving toward a universal
influenza vaccination recommendation was not new; it was published in
the *MMWR* ACIP influenza statement a few years ago, before Chiron had
its production problems. There was lingering concern that next season's
influenza vaccine supply would be insufficient to meet the need for a
full recommendation, and that even "encourage" implied that ACIP had
reviewed all of the pertinent data.

**Vote**

**Encouraging annual influenza immunization part of a strategy to
achieve universal immunization**

**In favor:** Allos, Campbell, Finger, Poland, Stinchfield, Treanor,
Womeodu

**Opposed:** Beck, Gilsdorf, Marcuse, Lieu, Morse, Morita, Abramson.

Dr. Abramson voted no because that intent can simply be made part of the
statement. He also remembered that recusals had not been checked. Dr.
Treanor was uncertain if he had a conflict or not, as he had done a
clinical study for ID Biomedical, which is now owned by GSK. Dr.
Pickering stated that Dr. Treanor's vote would be removed, but even
without the recusal, the motion would have failed because it had failed
to receive a majority of the votes.

**The motion failed.**

Dr. Marcuse summarized that there was clear enthusiasm for the concept,
only division on its expression. Dr. Poland felt that he had achieved
conceptually what he wanted. He remained unpersuaded by the fears
expressed regarding the complexity of the current recommendations, and
commented that if safety concerns are valid, the last vote should be
revisited. His desire was to see ACIP move beyond its annual reactive
role, and to state a laudable public health goal that all would support.

Dr. Abramson summarized that the next statement would acknowledge that
ACIP is working toward the goal of annual universal influenza
vaccination in the U.S. He was not concerned about safety, but about
other issues that all needed consideration. Dr. Poland agreed with that
approach. Dr. Halsey cautioned ACIP about its recommend to discontinue
the use of adamantanes for fear that the recommendation could prompt the
manufacturers to stop making them. Dr. Halsey noted that adamantanes may
be effective for other influenza strains. Dr. Abramson welcomed that
point.

Dr. Poland moved to state that a strategy of universal influenza
immunization is being evaluated by the ACIP. The motion was seconded by
Dr. Lieu. Dr. Stinchfield suggested placing a sentence near the end of
the statement, to the effect that anyone who wants influenza vaccine
should receive it.

There was a vote on the statement, including tiering and incorporating
Dr. Halsey's point that the recommendation against the use of
adamantanes is based only on current virologic susceptibility, which may
change over time. The motion had already been seconded

**Vote**

**On the statement, including tiering and incorporating note that the
recommendation against adamantanes' use is based only on current
virologic susceptibility, which may change over time.**

**In favor:** Allos, Beck, Campbell, Finger, Gilsdorf, Lieu, Morse,
Morita, Poland, Stinchfield, Treanor, Womeodu

**Opposed:** None

**Abstained**: None (there was no conflict involved in these aspects)

**The motion passed.**

***VFC Changes Relevant To Influenza Vaccine***

Presenter: Dr. Greg Wallace, NIP

In past years, VFC only covered children at high risk and their
contacts, and vaccine was left over even in years of shortage. Current
changes to the VFC recommendation were:

-   A permissive recommendation for vaccine use among all those
    VFC-eligible children aged 6 months through18 years of age, with
    priority given to routine high risk groups when supplies are
    limited, and with the addition by ACIP in 2005 to add those with
    compromised respiratory function.

-   The first high risk group, 6 through 23 month-olds, will now say
    6through 59 month-olds.

-   Contacts will change from those of children aged \<2 years to
    children aged \<5 years.

-   The language for LAIV will be added to the statement, \"All healthy
    children age 5 through 18 years with priority when supplies are
    limited to...\" the contacts listed for TIV.

-   All currently licensed vaccines will be listed in the footnote.

*Discussion* included:

-   Vaccination will also be recommended for contacts of those children
    aged 24 through59 months.

-   Dr. Poland asked if there were any new data on anaphylactic
    reactions due to chicken allergy, since that evidence was found to
    be outdated for MMR. No one had that information; the influenza
    working group will look into it. If it cannot be determined for this
    year, it will be addressed next year.

Dr. Finger **moved to approve the VFC resolution with the changes
described.** Dr. Poland seconded the motion.

**Vote**

**In favor:** Allos, Beck, Campbell, Finger, Gilsdorf, Lieu, Morse,
Morita, Poland, Stinchfield, Treanor, Womeodu, Abramson

**Opposed:** None

**Abstained**: None (there was no conflict involved in these aspects)

**The motion passed.**

***Update on HHS Pandemic Influenza Planning***

Presenter: Dr. Bruce Gellin, Director, NVPO

A national strategy for pandemic influenza was released by the President
on in November 1, 2005, and the Department of Health and Human Services
(HHS) pandemic influenza plan was released the next day. The
implementation preparedness plan for activities across the federal
government will soon be released. Preparedness activities for seasonal
influenza and pandemic are aligned.

Of the \$7.1 billion proposed for pandemic preparedness, \$6.7 billion
was for HHS. Congress provided \$3.3 billion in December, and the
President\'s budget for 2007 proposed another \$2.3 billion for this
coming year (the second year of funding of the original budget plan).

*Federal Roles.*

-   The largest aspect of preparedness is the creation of a stockpile in
    bulk of 20 million courses (2-doses) of vaccine against the most
    likely pandemic threat, by February of 2006 (currently there are 8
    million doses of H5N1 vaccine, at 90 mg/dose).

-   Creation of a domestic influenza vaccine manufacturing capacity
    sufficient to produce 300 million courses within 6 months of a
    pandemic onset is being examined; as is increasing egg-based
    capacity and accelerating cell-based production capacity,
    retrofitting existing manufacturing facilities for emergency
    influenza vaccine production, accelerating the development of dose
    sparing techniques (e.g., adjuvants, immune stimulants, delivery
    technologies), and developing a broad spectrum influenza vaccine.

-   A Request for Information (RFI) was posted on January 30, 2006,
    regarding efforts to expand existing egg-based influenza vaccine
    manufacturing facilities, to build new facilities, to convert
    existing manufacturing facilities that produce FDA-licensed vaccines
    and biologics to produce influenza vaccines, and to advance the
    development of recombinant-based influenza vaccines. Responses are
    due in February.

-   The goal of the Strategic National Stockpile (SNS) of antivirals is
    to be able treat 25% of the U.S. population with antivirals (75
    million treatment courses), reserving another 6 million for
    containment uses. There is full funding for 50 million doses and to
    subsidize the states' 25% of the remaining treatment courses.

-   An RFI was posted last year, and some responses have been received,
    to develop new prophylactic or therapeutic agents to prevent or
    treat influenza virus infection. With the resistance to adamantanes,
    only neuraminidase inhibitors are left as treatment. The treatment
    criteria include shelf life, efficacy, bioavailability or half life,
    and, oral or parenteral delivery.

-   More than 100 subject matter experts at CDC are working on pandemic
    preparedness.

*State roles.* The states were allocated \$350 million in the recent
emergency pandemic influenza appropriation passed by Congress in
December. Each state will receive at least \$500,000, with additional
funds allocated by population. New York City, Chicago and Los Angeles
County will receive supplemental grants. The balance of the \$250
million appropriated will be awarded later in 2006 based on progress and
performance. States and municipalities will use these funds to
accelerate and intensify current planning efforts for pandemic influenza
and for plan exercises.

Other FY06 budget priorities include expansion of FDA's regulatory
science base, enhancing the SNS (with personal protective equipment,
ventilators, etc.), increasing CDC\'s influenza lab capacity, expanding
domestic biosurveillance and situational awareness, advancing the
development of rapid diagnostics, and expanding education and risk
communication activities. In addition, the U.S. contribution of global
pandemic preparedness is \$334 million.

***NIH/NIAID H5N1 Update***

Presenter: Dr. George Curlin, NIAID/NIH

*Trials.* Of NIH's current \>100 ongoing active clinical trials, \>33%
are exploring a pandemic strain vaccine. Vaccine options include
inactivated vaccines similar to TIV, live vaccines similar to LAIV, and
inactivated vaccines with novel adjuvants and routes of administration.
Inactivated vaccine has a proven technology and the largest
manufacturing capacity, and its licensing would be simpler. Multiple
doses probably will be required.

*Safety/Efficacy.* Past experience with H5 vaccine development includes
the response to the initial Hong Kong outbreak. The Hong Kong H5-based
vaccine is predictive for the current vaccine trials (i.e., higher doses
give a better response, but all doses give some response.) Second-dose
data are needed. The current trial of the rgA/Vietnam1203/04 (H5N1)
vaccine involves healthy adults ages 18-64 years in a prospective,
randomized, double blind study. Two intramuscular (IM) doses are given
at a 28 day interval. The antigen range is broad, from 7.5 to 90 mcg,
and the end points are safety and immunogenicity (neutralization titer
of 1:40). To date, the vaccine has been well tolerated, producing some
neutralizing responses at all doses, but the highest doses gave the best
response (a 45--90 mcg dose was "acceptable").

*Immunogenicity.* Several strategies are being explored to overcome poor
vaccine responsiveness: administering a priming dose, incorporating
adjuvants, and using alternate administration methods including
intradermal (ID) vaccination. In Europe, 30 mcg doses of the H5
formulation have been found effective with an alum adjuvant, but in
normal interpandemic vaccines used at NIH, the alum has poorly enhanced
immunogenicity. The current study (DMID 05-0217) is a dose ranging study
on a constant alum vaccine formulation among healthy adults. The MF59, a
proprietary adjuvant in use, has been promising.

*Route of delivery.* Intradermal vaccination was studied previously,
comparing 15 mcg delivered IM versus 6 mcg delivered ID. The latest
study compares 3 mcg and 9 mcg ID. No difference was seen in the
previous study in those persons aged 18-60 years, but the IM delivery
was much more effective than ID in those persons aged \>60 years.

*Formulation.* Studies of live attenuated vaccines are also underway,
and some cold-adapted H5, H7, and potentially pandemic strains have been
developed. These vaccines are of interest because they are highly
immunogenic in susceptible populations (although correlates of
protection need to be defined); they can potentially be used at low
doses, and their induction of mucosal immunity might reduce
transmission. They also may offer some cross protection. However, they
are not licensed in all population groups; more safety data are needed;
as are correlates of immunity that could be extended to the elderly.
Other concerns involve issues of transmission and reassortment.

The experimental pandemic vaccines include nasal inactivated vaccines,
cross-protective peptides and epitopes, virus-like particles,
alternative live vaccines, vectored approaches, and DNA vaccines. But
the current critical question in the search for a pandemic vaccine is
whether the H5 hemagglutinin is intrinsically less immunogenic in
humans. Its biological mechanism is unclear. NIH is awaiting Australian
data which reportedly indicate a good vaccine with an alum adjuvant,
based on the Vietnam strain.

The vaccine development pipeline to date includes:

-   Sanofi pasteur and Chiron have submitted the current vaccine trial
    data for publication. Higher doses generated acceptable response.
    There are data on healthy adults and ancillary populations are
    already under study.

-   Sanofi pasteur's vaccine trials have completed enrollment in the
    elderly study, and enrollment is underway for the children's study.
    Sanofi pasteur's H5N1 vaccine with adjuvants is being studied among
    healthy adults (DMID 05 0127) and older adults (DMID 05 0141).

-   Chiron's H5N1 M59 was very immunogenic with the H9 strain. They are
    awaiting an import license to begin trials.

-   A booster dose to the current two-dose H5N1 vaccinees with the
    sanofi pasteur H5N1 vaccine is being done to assess its benefit.

-   Also planned, but on hold, is a study to add the H5N1 to the routine
    annual vaccine for healthy adults.

*Discussion* included a question of how far in advance a vaccine can be
developed before the virus has been identified as a pandemic strain;
whether the 20 million vaccine doses for the stockpile will be developed
before then; and, if so, what was expected of the vaccine's efficacy.
Dr. Curlin responded that the Vietnam strain, which has spread to
Eastern Europe and Africa, is apparently fairly stable. The hope is that
this virus will sufficiently protect from any new strain, should a
pandemic occur. Dr. Gellin added that the annual influenza vaccine
formulation also is based on the most recent strain, hoping that this
would provide cross-protection to any strain deviation. But should a new
strain emerge, a new vaccine would have to be developed. This situation
is occurring currently, where a prototype vaccine is now being developed
using one selected clade of the two current H5N1 clades. Slightly less
than 8 million doses have been manufactured this year by sanofi pasteur
and Chiron; the pandemic vaccine cannot be manufactured until production
of the annual strain ends. As a result, commercial scale manufacturing
of the pandemic strain will have to wait until next fall. But with
increased manufacturing capacity, the prepandemic vaccines perhaps could
be made while the companies produce the annual vaccine.

**TETANUS-, DIPHTHERIA TOXOID, ACELLULAR PERTUSSIS VACCINES**

***Report from the Pertussis Working Group***

Presenter: Dr. Dale Morse, Pertussis Working Group Chair

Overview: Review of ACIP Pertussis recommendations

The ACIP recommended protecting adolescents aged 11-18 years against
pertussis in June 2005, by giving one dose of Tdap rather than Td. The
Tdap dose was encouraged even if the Td had already been given. An
interval of \>5 years between Td and Tdap also was encouraged, but
shorter intervals could be used. In October 2005, the Working Group
discussions of a recommendation for adults aged 19-64 years produced the
following suggestions:

1.  Adults aged 19-64 years should receive a single dose of Tdap, in
    place of the next Td, to reduce pertussis among adults and reduce
    transmission of pertussis to infants. An interval \<10 years since
    the last Td can be used for booster protection against pertussis.
    The safety of an interval as short as \~ 2 years between Td and Tdap
    is supported by a Canadian study.

2.  Adults who have or will have close contact with an infant \<12
    months of age (e.g., parents, grandparents, childcare providers,
    health-care workers) should receive a single dose of Tdap at an
    interval shorter than 10 years since the last Td, to protect against
    pertussis. Ideally, they should be vaccinated ≤1 month before close
    contact with the infant. (Cocooning)

3.  Interim guidance regarding pregnancy was: "Women should receive a
    dose of Tdap in the immediate post-partum period if they have not
    previously received Tdap."

On this day, the Working Group presented the issues related to Tdap use
among health care workers and adults aged \>64 years. In June,
presentations are scheduled on the issues related to the use of Tdap
among pregnant women (adolescents and adults), and an ACIP statement on
that will be proposed.

The purposes of Tdap vaccination of adults are to:

1.  Protect them from pertussis morbidity.

2.  Decrease pertussis exposure to persons at increased risk of severe
    pertussis and its complications, especially infants aged \<12 months
    and adults with co-morbid conditions.

3.  Reduce the cost and disruption of pertussis in institutional
    settings.

4.  Reduce the reservoir of pertussis.

Considerations related to these objectives are that Tdap is licensed as
a single-dose vaccine. Its duration of immunity wanes at \~5-10 years
after vaccination and infection, which makes the need for a \~10-year
Tdap booster probable. Finally, the vaccine could cost \~\$20 more than
Td. Tdap is expected to be effective in stopping transmission, but how
that will be shown in the population is unknown. Currently, Td coverage
among adults aged 19-64 years is low, at only\~55%-67%, and is \~42%
among in those aged \>65. Tdap is not licensed for use in those aged
\>65 due to a lack of data to support that.

The Working Group advised ACIP to recommend Tdap at a short interval
after the last Td for healthcare workers with direct patient contact in
hospitals or ambulatory care settings, and to allow permissive use of
Tdap among adults aged \>64 years, even thought this is an off-label
use.

***Manufacturer Updates***

-   *sanofi pasteur* Dr. Michael Decker reported that Sanofi Pasteur is
    revising study protocols to provide data in \~3 years that will
    support licensure of Adacel™ with no upper age limit. Study
    enrollment is under way in Germany to assess Adacel™ given as the
    sixth consecutive dose of acellular pertussis vaccine; the five
    previous doses were given as Tripedia®. A similar Adacel™ study will
    be done with U.S. and Canadian cohorts as soon as they age to the
    lower age limit for Adacel™, expected in \~1 to 1½ years. A safety
    study of repeated Adacel™ administration will be done in a
    population that first received Adacel™ \~4½ years ago to provide an
    evaluation of the safety of re-administration after a 5-year
    interval.

-   *GSK.* Dr. Friedland reported post-marketing studies are underway of
    Boostrix® co-administered with MCV4. GSK is working with FDA to
    expand the licensed indication for Boostrix® beyond aged 18 years of
    age. A study of six consecutive doses with Boostrix® has been
    completed and is described in the package insert.

    ***Tdap Use Among Adults Aged \>65 Years***

Presenter: Dr. Katrina Kretsinger, NIP

> Overview: Review of the scientific rationale for permissive-use of
> Tdap among adults \>65 years of age, the current standard of care,
> considerations from the program perspective, and proposed wording.
> Older American adults have the highest tetanus case incidence and
> mortality; improving vaccination against tetanus and diphtheria is
> important.

*Vaccine.* Adacel™ (Tdap), made by sanofi pasteur is licensed for use
among persons from age 11 to 64 years as single-dose booster
immunization against tetanus, diphtheria, and pertussis. ACIP
recommended Tdap use in that age group. Adacel™ also is the only Tdap
licensed for use from age 19-64, as GSK's Boostrix® is licensed for ages
10-18. There are no prelicensure safety or immunogenicity studies for
Adacel™ use among adults \>65 years (older adults) who in 2002 comprised
12% of all Americans (\~36 million).

*Pertussis disease burden.* No prospective population-based study data
exist on pertussis incidence among older adults, but pertussis is
probably under-reported, as it is among younger adults. In a serosurvey
of 100 adults aged ≥65 years tested every four months for three
years,,10 developed *B.pertussis* infection as measured by antibody
rise, and half of those infected developed cough illness (Hodder *CID*.
2000;31:7-14).

Data of the National Notifiable Disease Surveillance System (NNDSS) from
1996-2004 were examined. In that period, 894 cases of pertussis were
reported among older adults; of these 8% were hospitalized and x-rays
indicated that 12% had pneumonia, a higher rate than that reported for
adults or adolescents. Four patients died, all of whom had
co-morbidities.

A 1992 pertussis outbreak in a Dutch religious institution had a 53%
attack rate of laboratory-confirmed clinical pertussis in its older
residents, four of whom died from pertussis-associated causes (Mertens,
*Eur J Clin Micro*. 1999; 18:242-247). The attack rate in a 1985
Wisconsin nursing home outbreak was 36% (Addiss, *JID*. 1991;
164:704-10).

*Pre-licensure safety and immunogenicity data* among adults 19 to 64
years of age were examined (in the absence of prelicensure data for
older adults). Also reviewed was preliminary data of an Austrian study
of Tdap administered with IPV among older adults, and VAERS reports.

-   *Td506.* The principal Adacel™ safety and immunogenicity study
    Td506, randomized persons aged 11-64 years to receive either sanofi
    pastuer Td or Tdap (both have the same diphtheria and tetanus toxoid
    quantities). Data were gathered for four pre-defined age groups
    (11-17, 18-28, 29-48, 40-64), as well as from an ad hoc subset of
    adults aged 60-64 years.

-   *Td506 safety data* were charted for local reactions (pain, erythema
    and swelling) for the four age groups from vaccination to 14 days
    later. Reports of pain decreased with the recipients' increasing
    age, rates of erythema and swelling were constant, and fever rates
    were generally lower for adults than adolescents. Serious adverse
    events (AE) were followed for six months, and were 1.9% for both Td
    and Tdap recipients. The U.S. Adacel™ prelicensure safety studies
    had two serious adverse events that were possibly related to Tdap;
    both resolved without sequelae.

-   Unpublished *Austrian Tdap-*IPV combination vaccine (Repevax™)
    immune-response study data were reviewed. Repevax™ has the same Tdap
    composition as Adacel.™ The study enrolled 252 healthy adults aged
    59-91 years; all had had Td boosters but no pertussis vaccine. They
    received one dose of Repevax™. Pre-defined immunogenicity and safety
    endpoints were not primary study objectives. Written AE reports were
    solicited 5 weeks after vaccination (recall that in Td506 AEs were
    solicited at 14 days after vaccination. The Austrian cohort on
    average were older (59-91 years) than the Td506 cohort (48-64
    years), and had about half the AE rates found in Td506. Comparison
    of the two studies should be interpreted with caution because these
    studies were conducted under different protocols, by different
    investigators, and using different evaluation criteria.

-   *VAERS* is a national, passive surveillance system for reporting
    adverse events following vaccination. No disproportionate rate of
    adverse events among older adults is reported after Td and TT among
    older adults compared with younger adults (Lloyd JC et al. *Vaccine*
    2003; 21). Reports of Guillain Barré Syndrome (GBS) and extensive
    limb swelling are rare after Td in older adults.

-   *Immunogenicity* *to tetanus and diphtheria toxoids after Tdap.*
    Immune responses to tetanus and diphtheria toxoids were reviewed
    separately from immune responses to pertussis antigens because the
    serologic correlates of protection for tetanus and diphtheria are
    defined, Tdap was seroprotective against tetanus and diphtheria and
    the booster-responses met the noninferiority criteria for Td among
    adults aged 11-64. Presented tables showed unpublished data for
    adults aged 60-64 years, demonstrating the same high seroprotection
    for Tdap as for Td. Although the response to tetanus and diphtheria
    toxoids was adequate from age 49-65 years, antibody responses to
    both toxoids declined with advancing age.

-   *Immunogenicity* *to pertussis antigens after Tdap.* Serological
    correlates of protection for pertussis are not well accepted. The
    Tdap (Adacel™) licensure for 11-64 year-olds was based on inferred
    efficacy from the boosting response in adults with serologic bridge
    to the immune response to three doses of DTaP among Swedish infants.

-   Pre- and post-vaccination geometric mean titers (GMTs) from older
    adults in the Austrian study of Tdap-IPV were compared with results
    from the ad hoc subset of adults aged 60-64 years from Tdap arm of
    the U.S. principal pre-licensure study (Td506). Both studies showed
    older adults had an immune response to pertussis antigens. In the
    principal pre-licensure trial Td506, the GMTs by age category showed
    that levels of filamentous hemagglutinin and pertactin remained
    relatively constant with increasing age, but levels of pertussis
    toxoid and fimbriae 2 and 3 declined with increasing age.

In summary, the pertussis burden among older adults is not well defined
but likely substantial. No U.S. trials of Tdap have been conducted among
older adults, but other related data do not suggest safety concerns; AE
rates are similar or decline with increasing age. Based on results among
aging younger adults, tetanus and diphtheria immunogenicity are likely
to be similar after Tdap and Td for older adults, but data specific to
this group are lacking.

The *rationale for permissive use of Tdap* include the following: use of
Tdap is consistent with and would reinforce the existing standard of
care for the recommended tetanus and diphtheria decennial booster, Tdap
would provide pertussis protection standard for care for older adults
who are in contact with infants (e.g., grandparents or be healthcare
workers), and Tdap would allow programmatic flexibility and provide
guidance for clinicians.

The *disadvantages of permissive use of Tdap* include the increase in
cost over the cost of Td for older patients, and that its use would be
off label. In the past, the ACIP has made off-label recommendations for
special populations and vaccine situations, such as use of *Haemophilus
influenzae* type b conjugate vaccine for immunocompromised adults, and
use of DTaP at age 12 months (given a 6-month interval) for a child
unlikely to return for the 4^th^ dose scheduled at 15 to 18 months of
age. Some past ACIP vaccine recommendations included routine use among
older adults when the vaccine was licensed without upper age restriction
(e.g., influenza vaccine, Td, and PPV-23).

The working group proposed permissive use of Tdap among older adults, to
be accompanied by information describing available safety and
immunogenicity data, and information to ensure that the standard of care
for tetanus and diphtheria are maintained through use of either Td or
Tdap. The working group also proposed that ACIP include a specific
recommendation for additional studies on Tdap safety and immunogenicity
among older adults as a basis for any future recommendation.

*Proposed recommendation.* The suggested wording was as follows:

> "Tdap is not licensed for use among adults \>65 years of age.  The
> safety and immunogenicity of Tdap among adults \>65 years of age were
> not studied during U.S. pre-licensure trials; data from clinical
> trials among older adults are limited (see section, Tdap among Older
> Adults). Clinicians can choose to administer Tdap to adults \>65 years
> of age for protection against pertussis in addition to protection
> against tetanus and diphtheria.
>
> "Recommendations for use of Tdap in adults \>65 years will be updated
> as new data become available.
>
> "All adults, including adults \>65 years of age, should receive a dose
> of tetanus toxoid- and diphtheria toxoid-containing vaccine every 10
> years for protection against tetanus and diphtheria, and as indicated
> for wound management."
>
> (Areas of future research related to Tdap and adults): "\... Studies
> are needed to establish the safety and immunogenicity of Tdap among
> adults aged \>65 years to support an evidence-based recommendation for
> use of Tdap among older adults..."

*Discussion* included points in favor of permissive use of Tdap in older
adults:

-   Dr. Plotkin appreciated, to general agreement, the cocooning
    strategy of protecting infants by vaccinating parents and
    grandparents.

-   Dr. Schaffner advised against limiting Tdap by age group, which
    risks further confusing internists and the public. Although the
    issues of safety and immunogenicity need to be addressed, he thought
    them unlikely to be substantive, and few internists would hesitate
    to give Tdap to patients aged 66 as well as 64.

-   Both Dr. Decker and Mr. Hosbach said ACIP's decision would not
    affect their plan to study Tdap in older adults. They anticipated it
    will require 2-3 years to complete the study and obtain FDA
    licensure.

-   Dr. Tan liked the permissive language and favored letting physicians
    choose, especially since the following text states that
    recommendations will come, pending data.

> Points opposed to permissive use of Tdap in older adults included:

-   Dr. Baylor commented that this recommendation varies from the
    FDA-approved label, which was based on the available data. He noted
    that studies have begun or are ongoing in these populations, and
    data will be available sooner rather than later. Additionally, the
    proposed recommendation is generic for Tdap, not a specific product.
    The GSK product is licensed only to age 18, a big difference to
    age 64. (Dr. Kretsinger noted that the recommendation for adult Tdap
    use only applied to one product, Adacel,^TM^ and that this is
    clearly stated in the adult recommendations.)

-   Dr. Abramson commented that ACIP only has recommended off-label when
    there was no chance of getting the needed data, something not the
    case here. Dr. Lieu agreed.

-   Dr. Pickering commented on the very small number of participants in
    the studies, none of whom were in the full targeted age group, and
    the great difference in the U.S. and Austrian studies. He found the
    recommendation to be too subjective. He agreed with other comments
    that the studies are being done and clinicians already can vaccinate
    this older age group against pertussis if they so choose.

-   A permissive use statement would not tell internists they shouldn't
    use the vaccine but rather that it would state that evidence
    supporting use of the vaccine among older groups is not available.
    Regardless, discomfort with a "recommendation" contrary to FDA
    licensure remained, Further, few studies provide evidence that older
    adults are an important source of pertussis for infants, which
    leaves the benefit of vaccinating older adults hypothetical for
    cocooning. Similarly, few or no studies provide evidence that older
    adult care providers are a source of pertussis for infants in child
    daycare.

-   Neither Td nor Tdap is paid for by Medicare for preventive care.

-   Dr. Pickering recalled the DTaP/Hib vaccine discussion when
    permissive off-label use of DTaP/Hib was released. He indicated that
    if a statement like this had been released, hundreds and maybe
    thousands of children would not have been properly immunized again
    Hib.

-   Dr. Jeff Duchin, of NACCHO noted that the pertussis burden of
    disease is not significant in older adults, nor a large factor in
    transmission, negating any urgency to recommend at this time.

*Alternatives suggested* were:

-   Dr. Campbell suggested deleting the last sentence of "Clinicians can
    choose to administer..." and the next two paragraphs about updates
    and the decennial booster. She proposed adding, "We recognize that
    vaccinating this population will likely be important to full
    implementation of a cocoon strategy."

-   Dr. Wexler suggested saying, "While not specifically recommended by
    ACIP for use, or licensed by FDA at this time, clinicians can choose
    to administer..."

-   Dr. Temte urged caution, especially in view of ACIP's development of
    evidence-based classifications for its recommendations. He had heard
    no data on rates of transmission between grandparents and infants;
    and the pending product is for adolescents, the highest transmission
    group. Clinicians have the right to treat as they see fit, but they
    look to ACIP for evidence-based guidance.

Dr. Finger **moved to amend the proposed recommendation language by
striking the sentence beginning with the word "Clinicians\..."** The
motion was seconded by Dr. Campbell.

Dr. Morse reported the Working Group's minor concern about safety in
this age group, and wish for more of a science base of exposed children.
But they concluded that the sentence does not really matter, since
physicians can vaccinate anyway as soon as it is licensed.

Dr. Allos observed (and Ms. Stinchfield agreed) that if the
"clinicians..." sentence is dropped, the recommendation would read more
like a caution against using the vaccine in people aged \>65. Waiting to
weigh the benefits and risks may do more harm. She suggested saying,
"The ACIP would like to recommend use of this vaccine in those aged
\>65, but cannot do so until data are available. That is anticipated in
\~2 years." That would convey this as an option to physicians about the
newborn as well as to grandparents.

**Vote**

**To approve the amended recommendation text.**

**In favor:** Campbell, Finger, Gilsford, Lieu, Marcuse, Morita,
Abramson

**Opposed:** Morse, Poland, Stinchfield, Womeodu

**Abstained:** None

**The motion carried.**

***Tdap Use Among Healthcare Workers***

Dr. Tejpraptap Tiwari, NIP

> Overview: Rates of pertussis among health care workers, transmission
> in health care settings; related costs.

Protecting the 8-10 million U.S. healthcare workers from acquiring and
transmitting infectious diseases is a public health goal. Adult
pertussis morbidity is substantial and includes cough for ≥3 weeks for
80%-100%. It can cause urinary incontinence in \~39% of women, rib
fractures in \~4% of adults, and syncope in \~3%. Although data
describing the incidence of pertussis among health-care workers are
limited, a few studies have been conducted. Four were outlined:

1.  Of 93 pediatric hospitals surveyed in 1994 by Lane et al (*ICHE*
    1997;18:400), 90% of the 62 respondents reported cases of pertussis
    within the past 5 years. Of those, 11% reported one or more
    physician contracted pertussis after exposure to a patient; data on
    other health care workers was not reported.

2.  Deville et al (*CID* 1995; 21(3):639) reviewed conducted annual
    serosurveys for pertussis from 1984-1989 in a tertiary care
    hospital. Fifty-one health-care workers were infected (based on
    elevated anti-PT titer) for a mean annual rate of 8%, and range from
    4%-16%. Re-infection was common. The rate of symptomatic pertussis
    was not reported.

3.  Wright et al (*ICHE* 1999; 20\[2\]:120-3) conducted a serosurvey of
    145 health-care workers in a 660-bed tertiary care hospital from
    1992 to 1994. Sera were obtained from emergency department (ED)
    personnel and resident physicians. The rate of symptomatic infection
    was 40%. Recent infection occurred among 7.6% of ED personnel and 2%
    of residents. The annual incidence of pertussis among ED personnel
    was 3.6/100 person-years and among residents was1.3/100 for
    residents.

4.  De Serres G.( *J Infect Dis* 2000;182:174) found a 1.7-times
    increased risk of pertussis among health-care workers in Quebec
    compared with the general population. Eight percent of adult
    pertussis cases from July to December 1998 were among health-care
    workers, even though health-care workers comprised only 5% of the
    adult population

*Health-care worker role in transmission.* CDC data indicate that a wide
range of positions among health-care workers acquire or transmit
pertussis, but they have in common direct contact with patients and
direct contact with other healthcare workers. The two primary factors
that foster transmission are delayed diagnosis and treatment in the
source case, and late implementation of control measures. The intensity
of contact has varied by setting. Outbreaks in each were described, for
hospitals' pediatric and adult settings, ambulatory care pediatric and
adult settings, and a long-term residential care facility for
developmentally disabled adults. A table of reported pertussis outbreaks
in pediatric settings (13 studies) showed three outbreaks beginning with
a health care worker; two beginning with infant to health-care worker,
and 8 beginning with an infant with pertussis. Although 7 pertussis
outbreaks in adult-care settings had health-care workers for all the
index cases, in three of four long term care residential facility
outbreaks patients were the index cases in three, and the index case was
not identified in one.

Six studies of health-care workers with pertussis in pediatric hospitals
showed cases transmitted by health-care workers before the illness was
recognized. The majority of secondary cases were among health-care
workers. However, secondary cases among infants occurred and resulted in
substantial morbidity, e.g., an infant with hospital-acquired pertussis
required mechanical ventilation for \>2 weeks and required another 2
months of hospitalization. When pertussis was recognized, investigation
identified a large number of contacts who required post-exposure
prophylaxis. In one outbreak (Martinez et al) the number of cases and
contacts was so large that the hospital chose to give chemoprophylaxis
to 3179 employees. Four studies (Jankelovich, 2006; CDC, 2005; Friedman,
2005; and McCall, 2002) described health-care workers and patient
exposures in adult-care settings that began with a single health-care
worker; secondary cases were prevented by existing control measures.

*Costs.* Pertussis control guidelines (CDC/HICPAC, *MMWR* 2003; HICPAC,
*AJIC* 1998; CDC 2000) advise hospital infection control practitioners
identify close contacts, provide post-exposure prophylaxis, test and
treat symptomatic employees and patients, and furlough symptomatic
employees for the first five days of treatment. These activities are
labor intensive and costly. The charted costs of outbreaks at three
hospitals (general, general with adult and pediatric beds, and
pediatric) ranged from \$64,000 to \$106,000 in direct costs; from
\$3500 - \$21,000 in cost per case; \$97-\$144 per exposure. Indirect
costs for personnel hours lost ranged from \$11,000 to \$68,000, and
\$97-\$180 in per case. Total costs ranged from \$75,000-\$174,000.

***Cost-Benefit Analysis of Tdap Vaccination of Health-Care Workers***

Presenter: Dr. Ismael Ortega-Sanchez, NIP

> Overview: Analysis of potential cost savings from preventing pertussis
> among vaccinated health-care workers, without change in control
> practices (given that Tdap's effectiveness to prevent subsequent
> transmission from vaccinated health-care workers is unknown).

Pertussis in health-care workers and nosocomial pertussis outbreaks are
a special concern in health-care settings because transmission can occur
to patients vulnerable to severe pertussis. Vaccinating health-care
workers will prevent the morbidity of pertussis. In addition,
vaccinating health-care workers may 1) reduce pertussis infections and
outbreaks in hospitals, 2) decrease transmission and prevent secondary
cases, and thereby reduce outbreak size and duration, and 3 ) reduce the
infection containment costs. The last includes case- and contact
tracing, post-exposure prophylaxis, and/or treatment of
hospital-acquired pertussis cases

To determine if cost savings might be possible from a program to
vaccinate health-care workers against pertussis, a probabilistic model
was used assuming 1000 hypothetical health-care workers with direct
patient contact, followed for ten years. Probability distributions were
specified for key parameters using a range of values, and varied
simultaneously using Monte Carlo simulations. Results were reviewed for
the following outcomes: number of nosocomial pertussis exposures;
vaccination-produced net costs or savings from prevented pertussis,
according to a hospital perspective. Health costs and benefits were
calculated in 2004 dollars with a 3% discount rate. Net costs (or
savings) accrued to the vaccination program and benefit-cost ratios were
estimated.

*Model assumptions*: The model assumed 1) no change in post-exposure
control measures, including antimicrobial prophylaxis, and 2) an annual
turnover rate of 16% of the 1000 health-care workers, and 20% of the
original cohort left by year 10. To maintain a stable population in the
model, those leaving each year were assumed to be replaced by new,
mostly unvaccinated healthcare workers. In the model, 66% of health-care
workers were vaccinated at the beginning of the first year. Since some
health-care workers who were vaccinated would leave, to maintain
protection levels would require vaccination of new health-care workers
at the beginning of each year. This progression was outlined on a
decision analysis chart, which also included possible vaccine failure,
and subsequent exposures.

The literature provided values and ranges for the annual rate of *B.
pertussis* infection in health-care workers, the proportion of these
infections that would be symptomatic, the number of hospital contacts
exposed by each symptomatic health-care worker, and infection control
costs per exposure. The cost estimates were comprehensive, including
contact tracing, laboratory work, antimicrobial treatment and
health-care worker furloughs. The literature provided data on vaccine
efficacy and coverage, adverse events, vaccine cost, as well as the mean
values for employee turnover rates, etc.

Algorithms used to calculate the annual number of pertussis exposures
prevented, or not, per 1000 healthcare workers, with- and without a
vaccination program were described. Exposures were defined as the number
of patients and health care workers in the hospital who had direct
contact with the persons with pertussis. The number of exposures
prevented was the proxy for the number of cases prevented.

*Results.* After the Monte Carlo simulations of the number of exposures
resulting from health-care workers ill with pertussis, we selected the
median number of exposures and approximated a confidence interval using
the 5^th^ and 95^th^ percentile simulation values. With the Tdap
vaccination program in health-care workers, we estimated that a median
of 93 (46%) of annual exposures would be prevented, with a range of
13-310 exposures (5^th^ and 95^th^ percentiles). The calculated net
containment costs saved in a ten year period (cost of infection control
less vaccination costs, both discounted) was \$94,981 per 1000 health
care workers, with a range of a negative \$52,882 (5^th^ percentile) and
a positive \$534,807 (95^th^ percentile). The benefit-cost ratio of a
Tdap vaccination program from a hospital perspective was a \$2.38 return
for every dollar invested in the vaccination program for health-care
workers (\$0.36-\$10.86).

*Sensitivity analyses*. A multivariate regression analysis was done over
the range of simulation estimates to gauge the analysis' sensitivity for
pertussis exposures prevented and the benefit-cost ratio. The
statistically significant variables in order of their influence over the
model outcome were the number of exposed health-care workers, the
incidence of pertussis among health-care workers, employee turnover and
cost of the vaccine (both with a negative influence), vaccine coverage
and efficacy, and containment costs.

A line graph demonstrated the impact of symptomatic rates and the
incidence of *B. pertussis* infection on the benefit-cost ratio. Net
vaccination cost-benefits were achieved at a 6.7% incidence rate, if
≥15% of health-care workers are symptomatic, at 3.6% incidence rate if
\>28% of health-care workers are symptomatic, and at 2.5% incidence rate
if \>40% of health-care workers are symptomatic.

Threshold analyses were done to determine breakeven values for ten
variables, of which three were highlighted: vaccine cost per dose,
number of contacts exposed, and the health-care worker turnover rate. If
other factors were not changed, net savings from a vaccination program
were possible if, for example, the number of exposed contacts per
health-care worker was [\>]{.underline} 2.5 rather than 8.73 as in the
base-case, if the health-care worker turnover rate was \>100% rather
than 16% as in the base-case, or if the vaccine cost was \$84 rather
than \$30 as in the base-case.

Limitations of the analysis included the use of exposures as a proxy for
potential cases, possibly limited generalizability of the results, the
assumption of an inverse correlation of vaccine effectiveness and
coverage with the number of exposures and outbreaks, an assumed constant
ratio of health-care workers-to-beds, and an assumed constant hospital
occupancy rate. The model's strengths included 1) the assumed turnover
rate and continuous vaccination reduced the relevance of prolonged
vaccine effectiveness, and 2) the probabilistic modeling and threshold
analyses identified key uncertainties for future research.

*Conclusions* were that:

-   A Tdap vaccination program in health-care workers could have
    substantial impact in reducing hospital-acquired pertussis morbidity
    by reducing the number of annual exposures (-46%).

-   The benefits (or savings) from a Tdap vaccination program could be
    sizable for hospitals even after covering program costs (the
    benefit-cost ratio could be \>1).

-   Health and cost outcomes are highly sensitive to the number of
    persons exposed in the hospital per each symptomatic health-care
    worker, the annual rate of *B. pertussis* infection in health-care
    workers, and the proportion of workers who become symptomatic.

*Discussion* included:

-   The vaccine cost per dose was for vaccine only, not the program. Dr.
    Marcuse noted the far greater cost of a program, to which Dr.
    Ortega-Sanchez agreed. But even with an \$84 total cost, there could
    be benefit to the hospital. Dr. Hull added that the vaccination
    would be added to systems already in place to deliver other
    vaccines, so the increment would be far less than that of a new
    program.

-   Ms. Stinchfield noted that Dr. Tiwari's tertiary care hospital slide
    indicated 40% of adults are symptomatic with *B. pertussis*
    infection. That could include nasal carriage, but asymptomatic
    persons do not transmit.

-   The base case incidence in health-care workers was based on the
    serological studies presented, which came from in-house serologic
    analysis of antibody titers to determine the annual infection
    incidence range of 4%-16%.

-   Dr. Lieu commented that the presentations inferred a "slam-dunk"
    recommendation decision. She asked for any areas of controversy. Dr.
    Murphy identified two: the weak national data on incidence rates,
    among health-care workers, although outbreaks are well defined; and
    the unknown level of transmission prevented in vaccinated
    health-care workers. The vaccine may be efficacious against disease,
    but even a mild cough or respiratory symptoms may transmit.

    ***Proposed Tdap Recommendations***

Presenter: Dr. Trudy Murphy, NIP

> Overview: Rationale for recommending Tdap for health-care workers with
> short interval after the last Td; draft proposed recommendation.

The rationale to recommend one dose of Tdap for health-care workers at
short interval after the last dose of Td, rather than the General
Recommendations' ten-year interval, involves science, standard of care,
and programmatic aspects.

*Science.* Data indicate substantial morbidity of adult pertussis, and
health-care workers with direct patient contact are likely to be at
increased risk. Tdap prevents pertussis in adults. The current standard
of care supports Tdap vaccination of health-care workers because
pertussis immune health-care workers will decrease exposures and
secondary cases in both pediatric and adult-care settings. Tdap's safety
was demonstrated in a Canadian adolescent study that included intervals
as short as 2 years after the last Td booster. However, no data indicate
the duration of protection against pertussis in adults, or whether Tdap
vaccination of health-care workers will be an effective strategy to
prevent transmission.

*Standard of Care.* The standard of care supports Tdap vaccination of
health-care workers. ACIP already recommends worker vaccination to
prevent the transmission of vaccine-preventable diseases in health-care
settings, and ACIP already recommends that adults receive a single dose
of Tdap to replace the next decennial Td. ACIP has also recommended that
adults in contact with infants receive a Tdap dose at short interval
after the last Td, to protect the adult from pertussis and to prevent
transmission of pertussis to the infant

*Programmatic issues.* Facility infrastructure readily allows
implementation of a Tdap vaccination program for health-care workers, as
done for other vaccines such as influenza. The costs of vaccination will
be offset by reduction in infection control activities and medical
leave, and by increasing vaccination rates. A single, simple ACIP
recommendation can cover both pediatric and adult-care settings, and the
health care workers can be prioritized for vaccination (e.g., according
to infant- or direct patient contact). However, the vaccine will be an
incremental increase in expenses for facilities that now offer Td to
their staff, and a larger expense for those that do not. The necessary
education and vaccination program will incur substantial cost, and the
short interval from the last Td will increase implementation costs in
the short term, since more health-care workers will be eligible for this
vaccine than would be the case for a simple replacement for the next
scheduled Td decennial booster. Finally, the guidelines for
post-exposure prophylaxis of vaccinated health-care workers will require
review, as they were developed when adults were not vaccinated for
pertussis.

*Proposed recommendation.* The proposed text to recommend Tdap
vaccination for health care workers was:

> "Health-care workers who work in hospitals or ambulatory care settings
> and have direct patient contact should receive a single dose of Tdap
> as soon as feasible if they have not previously received Tdap.
>
> "Although Td is routinely recommended at intervals of 10 years, an
> interval as short as 2 years from the last dose of Td is recommended
> for the Tdap dose among health-care workers (see recommendation for
> "Short Interval between Td and Tdap").
>
> "These health-care workers include but are not limited to physicians,
> other primary care providers, nurses, aides, respiratory therapists,
> radiology technicians, medical and other students, dentists, social
> workers, chaplains, volunteers, dietary and clerical workers.
>
> "Other health-care workers (i.e., who do not work in hospitals or
> ambulatory care settings, or who do not have direct patient contact)
> should receive a single dose of Tdap according to the routine
> recommendation for use of Tdap among adults, if they have not
> previously received Tdap.
>
> "These workers are encouraged to receive the Tdap dose at an interval
> as short as 2 years from the last dose of Td (see recommendation,
> "Short Interval between Td and Tdap").
>
> "Vaccinating health-care workers with Tdap will protect them against
> pertussis and is likely to reduce transmission to patients, other
> health-care workers, household members and persons in the community.
>
> "Priority should be given to vaccination of health-care workers who
> have direct contact with infants aged \<12 months (see recommendation,
> "Prevention of Pertussis among Infants Aged \<12 months by Vaccinating
> their Adult Contacts")
>
> "Hospitals and ambulatory facilities are strongly encouraged to
> provide Tdap for health-care workers and to use approaches that
> maximize vaccination rates, e.g., education about the benefits of
> vaccination, convenient access, and the provision of Tdap at no
> charge.\*

*Discussion* included:

-   Ms. Stinchfield suggested adding nursing students to the list.

-   Dr. Finger proposed saying that "... hospitals and ambulatory care
    facilities should provide ..." rather than "are strongly encouraged
    to.."

-   Dr. Gilsdorf suggested inserting text indicating the potential cost
    saving, to lower CEOs' pain from the suggestion that the hospital
    pay for it.

-   The influenza statement provides a precedent for ACIP to say a
    facility "should" pay for the vaccine, even for populations that are
    not poor. The new HICPAC/ACIP health-care worker statement
    recommends that health-care workers' recommended vaccines be
    purchased for them, as does OSHA's requirement for health-care
    workers' hepatitis B vaccine. Dr. Carolyn Bridges added that a
    recent California study demonstrated a strong association between
    having a vaccination paid for and its uptake by health-care workers.

> Dr. Abramson summarized the general consensus to parallel the
> influenza statements' recommendation that hospital and ambulatory care
> facilities "should provide," rather than being "strongly encouraged to
> provide", vaccination. Further discussion included:

-   Dr. Myers noted that this would leave out nursing homes, hospices,
    EMS services, etc. He suggested using the influenza guidelines
    terminology of "health care personnel" as a catch-all, rather than
    distinguishing between facilities. Dr. Murphy reported that as
    discussed by the Working Group, but rejected due to the scarcity of
    information on nursing homes. The nursing homes' professional
    association also opposed it because of high turnover. She also
    reminded the committee that these health-care workers will be
    covered by the general adult Tdap recommendation. This wording was
    for catch-up pertussis vaccination of health-care workers in acute
    care facilities. Nonetheless, Dr. Myers advocated for ACIP's
    boldness, as Dr. Poland had earlier, to further avoid potential
    deaths among the elderly.

-   Dr. Duchin asked if any studies are planned to better define
    understanding the vaccine's efficacy in this setting. He was
    particularly interested since the ACIP has not recommended a change
    the current outbreak control and post-exposure prophylaxis
    protocols, which incur a significant cost to healthcare facilities.
    He also asked how transmission from unrecognized asymptomatic, or
    mildly symptomatic, health-care workers could be detected. Dr.
    Murphy responded that funding has been applied for to underwrite
    such studies. NIP would be glad to share its protocol with any
    facility, and greatly desires such data.

Dr. Allos **moved to accept the recommendation with the edits discussed
(i.e., saying "should provide" rather than "strongly encouraged to
provide", adding nursing students and ambulatory/acute care settings to
the recommendation.**

When Dr. Murphy reported that the definition of "acute care setting" is
variable between adult care physicians and pediatricians, Dr. Poland
**made a friendly amendment to define "ambulatory care settings" in a
footnote.** Ms. Stinchfield seconded that motion.

**Vote**

**To accept the proposed recommendation with edits.**

**In favor:** Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu,
Marcuse, Marcuse, Morita, Poland, Stinchfield, Womeodu, Abramson

**Opposed:** None

**Abstained:** None

**The motion passed.** Dr. Murphy stated that the ACIP recommendation
for health-care workers would be presented to HICPAC for a consensus
statement.

**HERPES ZOSTER (SHINGLES) VACCINE**

***Storage/Handling of Herpes Zoster Vaccine***

Presenter: Dr. Greg Wallace, NIP

> Overview: Issues of cold storage for herpes zoster, varicella, LAIV,
> and combined measles, mumps, rubella, and varicella vaccine (MMRV)

The herpes zoster (HZ) vaccine up for licensure requires freezer
storage. Three other current vaccines do so as well: varicella, proQuad™
(MMR-varicella) and live-attenuated influenza vaccine (LAIV). All must
be stored at -15◦ C (5◦ F). Varicella can be stored at 2º-8º C for up to
72 hours before reconstitution, as may LAIV for ≤60 hours before use. At
room temperature, varicella holds its minimum potency of 1350 PFU for
only 30 minutes after reconstitution. MMRV vaccine many not be stored at
2º-8º C for any period of time, and must be discarded after
reconstitution if not used within 30 minutes. LAIV vaccine cannot be
refrozen after thawing

The requirement to store vaccines in the freezer leads to storage errors
for both freezer-stored and refrigerator-stored vaccines. To determine
if a freezer storage requirement poses a problem, CDC conducted two
surveys of providers (\>700) and practices (221). They found in both
that 17%-18% of freezers are too warm at any given time *(Am J Prev Med*
2002;23(4):246-253; *Pediatrics* 2001;107(6):3100-104). CDC's guidelines
advise turning the thermostat of standard household-type refrigerators
to the coldest setting to maintain a -15º C temperature, but that could
make the refrigerator too cold. Careful monitoring is needed. The
refrigerator thermostat controls the volume of air going into the
freezer, although freezers control their own temperature. Some
refrigerators have temperature zones that vary.

With freezer storage for some vaccines, the old dormitory-style
refrigerators are no longer acceptable. About 30% of standard
refrigerator freezers used to store varicella vaccine were too cold, and
for inactivate vaccines, too-warm storage is less of a problem than
too-cold storage. HZ vaccine users will include providers inexperienced
in simultaneously maintaining vaccines in a refrigerator and a freezer.
If they are not a VFC site, the lack of inspections will leave that
uncorrected without a concerted education campaign by the Academies and
the professional societies.

Dr. Barbara Kuter, of Merck, reported their extensive education campaign
when varicella vaccine was first released. That included putting
information on the outside of the shipment box, on the vaccine vial
itself, and additional information in the box. They plan the same
activities for the zoster vaccine. Dr. Kelly Moore, of the Tennessee
Immunization Program, reported their extensive experience with
mishandled varicella vaccine that must be discarded yearly. They
recommend the small dorm-size, freestanding counter-high freezers, which
cost \~\$400-\$500, to maintain the cold temperatures needed by
varicella without compromising the refrigerated vaccines.

***Survey of Internists/Family Care Practitioners About Herpes Zoster
Vaccine***

Presenter: Dr. Allison Kempe, University of Colorado, Rocky Mountain
Prevention Research Center

CDC and the Vaccine Policy Collaborative Initiative conducted a survey
of internists and family care practitioners, randomly sampled to
represent the ACP and AAFP national associations, as well as geographic
regions, locations (urban, rural suburban), and setting (private
practitioners, etc.). They were surveyed in two sentinel provider
networks in November/December 2005, to determine:

-   The perceived burden of Herpes Zoster (HZ) and Post-Herpetic
    Neuralgia (PHN) in primary care practice

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-   The practitioners' intentions for recommending a new HZ vaccine if
    it is recommended by ACIP

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-   Perceived barriers to HZ vaccination.

The survey was administered over eight weeks by Internet or mail, based
on the provider's preference. The Internet and mail protocols were both
described. The initial contact information included an informational
paragraph about the clinical trial of the new herpes zoster vaccine
(Oxman et al, *NEJM* 2005). The survey was pilot-tested in community
advisory panel composed of internists and family medicine physicians
from across country.

The response rate was 62% (N=272) for general internal medicine (GIM)
practitioners and 76% for those in family medicine (FM, N=328). Email
surveys conducted by a Web-based survey company were selected by 66% of
the respondents. FM and GIM characteristics did not differ appreciably,
with \~80% in a private practice setting, although most family medicine
physicians were in rural areas. Survey results were as follow for
disease burden:

1.  *Number of zoster patients seen* in the last year, with- and without
    PHN (combined GIM/FM data): without PHN, a median of 3 each for
    patients aged 50-59 and ≥60 years; and 1 and 2 patients,
    respectively, with PHN. Both groups were immunocompetent.

2.  *Median visits to treat*: 2 with PHN, 4 without; referred to
    sub-specialty: None, 74% without PHN, 36% with it; referred 1%-9% of
    patients: 22% and 41%; and referred ≥10% of patients: 4 % and 23%,
    respectively. The specialties were ophthalmology (24%), dermatology
    (6%). Neurology (32%), and pain management (40%).

3.  HZ and PHN cause *significant burden of disease* in my older
    patients: 35% strongly agreed; 46%, somewhat; 19% somewhat or
    strongly disagreed.

Responses on vaccine use and recommending it were:

4.  *Vaccine use is warranted* for the burden of HZ and its
    complications in patients. GIM: strongly agreed: 15% for those aged
    50-59 years; 40% for those aged 60 to 79, 38% for \>80; FM: 17% for
    age 50-59 years; 29% for 60-79 and 28% for \>80.

5.  *GIM likelihood to recommend HZ vaccination:* ≥75% were very likely
    or somewhat likely for the two older groups and the severely
    debilitated; 76% were only somewhat likely or unlikely to vaccinate
    those 50-59 years old.

6.  *Likelihood of FM to recommend HZ vaccination*: The proportions of
    responses were similar to the GIM group, except they were more
    likely to recommend for the younger (50-59) age group, and their
    rate differences between likely and unlikely were less broad than
    the GIM group.

Only 15% responded to an open-ended question about groups the physicians
would consider off-label use among. They listed patients overtly or
functionally immunocompromised; those with chronic disease; those less
able to tolerate shingles, or with shingles history, especially if
severe; those who had varicella during infancy, immigrants; those who
could infect others; healthy persons aged \< 50 with varicella history;
and healthy children and adults susceptible to varicella

Barriers to vaccination were asked, according to definitely a barrier ─
somewhat of a barrier ─ not a barrier (N=595). Among the questions and
responses were:

-   Reimbursement/financing issues: Definitely a barrier, GIM, 31%, FM:
    44%, average 38%; somewhat of a barrier, 38%; not a barrier, 24%.

-   Patients unwilling to pay if not covered: 37% - 43% - 20%.

-   Up front vaccine purchase costs: 30% - 35% - 35%.

-   Patients will not think they need this: (23% - 45% - 33%.

-   Insufficient information about duration of protection: 22% - 40%
    -38%

-   Insufficient information about safety: 17% - 35% - 48%

Barriers identified by \<10% of providers included freezer storage;
physician concern about safely administering a live attenuated virus to
patients with chronic medical conditions; ineligibility of many patients
if FDA retains the trials' contraindicated groups; and contraindication
for use among immunosuppressed patients. Others included unknown
varicella disease status by patients not living in the U.S. for the past
30 years or foreign-born, and the potential for accidental vaccination
of a child.

Summary of findings:

-   About 80% of FM and GIM providers strongly or somewhat agreed that
    HZ and PHN cause a significant disease burden in their older
    patients.

-   A significantly higher percentage of physicians strongly agreed to a
    higher burden for patients aged 60-79 years, versus 50-59 years, to
    sufficiently to warrant a vaccine (FM 29% versus 17%; GIM 40% versus
    15%).

-   Overall, both FM and GIM providers were very- or somewhat likely to
    recommend HZ vaccination for all age groups, but significantly more
    would do so for patients aged ≥60 than those 50-59 years (FM 78%
    versus 60%, GIM 79% versus 57%).

-   The major perceived barriers to vaccination were financial (the top
    3; inadequate reimbursement, up-front costs, patient unwillingness
    to pay), followed by patients not perceiving the need and
    insufficient information about duration of protection and safety.

    ***Shingles Prevention Trial, Zostavax®***

Presenter: Dr. Paula Annunziato, Merck

> Overview: Epidemiology/medical need of HZ, severity and burden
> (medical and non-medical) of disease; study population for ZOSTAVAX®
> and Shingles Prevention Studies; ongoing and planned activities.

ZOSTAVAX® would be the first intervention to prevent HZ and its
complications, including PHN. Its efficacy and safety was demonstrated
in a pivotal study of participants aged \>60 years. FDA is reviewing its
license application now.

*Herpes zoster epidemiology* The increase of HZ incidence with advancing
age was clearly charted by decade, with almost half (46%) occurring
after age 60. PHN is the pain that persists after resolution of an HZ
rash. It occurs in 10-20% of HZ patients, but in ≤30-50% of those aged
\>60. Estimated prevalence is \~500,000 cases in the U.S., with new
incidence of 100-200,000 annually.

A study of pain severity (Katz J, Melzack R, *Surg Clin N Amer*
1999;79:231-52) was reported by patients with painful syndromes. The
pain scores of zoster and PHN were exceeded only by those for abdominal
hysterectomy and acute headache. HZ and PHN pain scores surpassed those
for childbirth, fibromyalgia, chronic cancer and musculoskeletal pain.

*Disease burden.* HZ causes 50-60,000 related hospitalizations annually
(average stay of 5-7 days) in the U.S., 12-15,000 of them with a primary
HZ diagnosis. Yearly, about 3 million HZ-related ambulatory care visits
occur, averaging 3 visits per episode, and 33% involve at least one
visit to a specialist. But HZ patients with pain for ≥90 days have \>10
visits on average. The non-medical burden in the U.S. includes work and
productivity loss, preliminarily estimated at an average of 3-7 days per
HZ case. That equates to \>600 to 750 thousand work days lost annually
in the 50-59 year old category alone. Quality of life is severely
affected in terms of physical, functional, social and psychological
status.

*Zostavax® clinical development program.* The Zostavax® clinical trial
enrolled \>20,000 participants, mostly Caucasian, gender balanced and
aged 30-99 years, with a variety of underlying medical conditions
(except for altered immune status or past HZ history). The largest study
in this program was the Shingles Prevention Study (SPS).

*Shingles Prevention Study (SPS).* This was a double-blind,
placebo-controlled, multi-center trial at 22 sites from November 1998 to
April 2004. A collaboration between the VA, NIH, and Merck, it enrolled
38,546 subjects ≥60 years of age who were age-stratified (from 60-69 and
≥70 years. Nine of ten subjects had ≥1 underlying medical condition. The
subjects were randomized equally between ZOSTAVAX^®^ or placebo. The
ZOSTAVAX^®^ was administered at its potency just prior to expiration, to
ensure a conservative conclusion. Monthly telephone follow-up was done
to identify HZ cases and to monitor adverse events (AE), and all
subjects were actively contacted at the study's end.

The most frequently reported prior medical conditions were arthritis and
hypertension, followed by a prostate disorder, allergic reaction, GI
disorder, hypothyroidism and hypercholesterolemia. Many other conditions
were also, but less frequently, reported. VE was assessed by HZ
incidence, PHN incidence, and zoster pain burden. The latter combined
the incidence, severity and duration of zoster-associated pain.

*Results* were as follow:

-   *Incidence of zoster,* compared to placebo, was reduced by 51.3%;
    PHN incidence dropped by 66.5%, and zoster pain burden of illness
    dropped by 61.1%.. Interestingly, VE differed against HZ according
    to age strata, being higher in the younger 60-69 year-old age group
    (63%) versus those \>70 (38%). VE against PHN and zoster pain burden
    of illness was similar between the two age groups. The greater VE
    for the younger age group appears to be from prevented HZ cases and
    their subsequent PHN and other complications. For the older age
    (\>70) group, the vaccine benefits are HZ cases prevented and pain
    amelioration for breakthrough cases.

-   To assess VE among more frail persons, the subjects\' baseline QALY
    scores related to functional limitations due to health status were
    assessed. About half the SPS subjects had at least some limitation
    in their functional status, defined among \~10% as moderate or
    severe. VE against HZ was well preserved in those groups, at \~50%
    among persons with self-rated mild, moderate, or severe limitation.
    The VE for PHN was similarly well preserved; the VE in these
    subgroups was \~60%, close to the 67% overall study VE. A similar
    \~60% VE against zoster pain burden of illness also was seen in
    these subgroups.

-   *Duration of protection*. The study subjects were followed for an
    average of 3.1 years (some for ≤5 years) to assess VE. The data
    showed it to be well preserved through year 4, but data are still
    too few to be conclusive. However, a trend was apparent for high VE
    after the first year of vaccination: 62% for HZ, 85% for PHN, and
    79% for herpes zoster burden of illness. The VE rises after year 1
    to be very stable on all three end points.

*Safety.* The ZOSTAVAX^®^ safety data were built on the extensive
VARIVAX^®^ safety database of 56 million doses distributed since
licensure in 1995. A clinical evaluation compared the \>20,000 subjects
vaccinated with ZOSTAVAX^®^ to \>19,000 placebo controls. The large
cohort and trial database allows study power sufficient for even some
uncommon adverse experiences (i.e., 97% power to detect events at 1.8
/10,000 frequency and 80% power to detect 0..8/10,000). Across eight
Zostavax® studies to date, the vaccine has been well tolerated.

-   *Adverse events* reported in the SPS were recorded and assessed
    during the trial and in the safety follow-up period to day 42. SAEs
    were evenly distributed between the number and percentages of
    patients across the vaccination groups (i.e., 255 in the Zostavax®
    group, 254 in the placebo group). An AE monitoring sub-study
    provided vaccine report cards for nonserious adverse experiences,
    which also were followed through the study for hospitalizations for
    any reason. That sub-study showed a difference in the number and
    percent of subjects who reported serious AEs (SAE), at 0.64 subjects
    in the Zostavax® group and 0.41 in the placebo group, which was
    statistically significant. But the reverse was also true, almost
    exactly, in the slight difference between the subjects who did not
    receive the vaccine report card, which balanced out the overall
    cohort. The Zostavax® group reported 191 SAEs and the placebo group
    reported 213.

-   The reported SAEs included five serious ones possibly related to
    vaccine: two in the Zostavax group (asthma exacerbation and a case
    of polymyalgia rheumatica) and three in the placebo group. Mortality
    was balanced between the two groups. The SAEs were listed by groups
    and were balanced overall. The most frequent was
    cardiovascular-related symptoms, at 0.4%, followed by general body-
    and central nervous system, and digestive systems, at 0.2%. For CVS,
    the smaller adverse event monitoring sub-study reports split, at 20
    in the Zostavax® group and 12 subjects in the placebo group; for
    CNS, 12 in the Zostavax® and 6 in the placebo group. There was no
    clustering of similar events.

*SPS non-serious events* included:

-   Local injection reactions were vastly higher in the Zostavax® group:
    at 48.3% versus 16.6% in the placebo group, but that is not
    unexpected in such a vaccine study. Systemic AEs overall were well
    balanced between the two groups, although there was some elevation
    in events of vaccine-related headache episodes. These were fairly
    low in frequency but were statistically significant, at 1.4% in the
    Zostavax group and 0.9% percent in the placebo group. All other
    vaccine-related events, including hospitalizations and deaths, were
    balanced between the two groups

-   *Inadvertent vaccination*: There were no seronegative subjects found
    in the SPS. Two protocols looked specifically for this in adults;
    Zostavax® 003 and Varivax®

-   *Rash*. Since Varivax® carries a small vaccine-associated rash risk,
    that was explored for Zostavax.® Analysis determined the
    post-vaccination rash rate to be much lower than that for Varivax®,
    with \~0.3% of subjects reporting one to day 42 after vaccination.
    Of those, only two had lesions containing the vaccine Oka strain
    VZV. However, those two subjects were not from the SPS, but from
    earlier studies. No PCRs done in the SPS to detect herpes zoster
    identified the Oka strain of VZV.

*Study 49*. Even in the tropical counties where 003 was conducted, only
21 of 1000 screened were seronegative. Protocol 49 also was an
international study, which found only 17 of 142 aged \>30 who were
varicella seronegative. So, no related safety issues were found upon
vaccinating these subjects, but it is very rare to find them.

*Ongoing/Planned ZOSTAVAX^®^* activities include the VA's continuation
of its durability of efficacy study among in SPS subjects (persistence
sub-study in 12 of 22 sites that should go out to ten years). Placebo
groups' participants are being offered Zostavax® vaccination. Two
clinical trials are ongoing; one a bridging study during the transition
from frozen vaccine to a refrigerated formulation, and the other a study
of concomitant administration of Zostavax® with inactivated influenza
vaccine.

# 

In anticipation of licensure, a risk-management plan is in place to
conduct postmarketing surveillance for adverse events, expand the
already existing VZV identification program to allow PCR analysis of
submitted clinical specimens, and expand the pregnancy registry to
include subjects who received Zostavax.®

# 

*Summary*. The extensive ZOSTAVAX® clinical database includes \>40,000
subjects enrolled in the clinical trail program, of whom \>20,000 were
vaccinated. The vaccine was shown to prevent HZ (VE=51%), PHN (VE=67%),
and reduce HZ pain burden of illness (VE=61%). Zostavax® efficacy
persists for four years postvaccination, to date; further data are hoped
to be released soon to extend that outer range. The vaccine elicits a
VZV-specific CMI response and has a an excellent safety profile

There was no discussion following this presentation.

**Public Comment.**

Dr. Collette Curtis is an anesthesiologist at Emory University hospital
who also works in pain management. She reported, of the many PHN
patients seen, the particular debilitation among the elderly population.
The pain has been described as like being burnt from within, and there
is little that can be done for it. She recounted one story, to
demonstrate how extreme the pain is, of a 70 year-old man who developed
PHN in his thoracic dermatome. There were no openings to see him, until
later that day, his son called demanding that he be seen, because he was
at the kitchen table with a gun to his head, threatening to shoot
himself. With our aging population, she expected to see many more
developing PHN, and strongly supported vaccine development to prevent
it.

Dr. Harry Strothers is a family physician and geriatrician, and is on
the faculty of Morehouse School of Medicine. He agreed with Dr. Curtis
about the personal aspect of PHN. The great difficulty of this
condition, as opposed to other pain syndromes, is that it does not
respond well to pain medications, and the patients become quite
desperate. Added to that is that many have other problems, such as being
immunocompromised, which make them even more debilitated and less likely
to leave their bed for physical therapy to keep them ambulatory.

**ACIP Evidence Based Recommendation Classifications**

Presenter: Dr. Daniel Fishbein, NIP

> Overview: Background and discussion of the process, major changes
> (already presented and new)

The classifications of evidence on which to base ACIP recommendations
have been in development since October 2003. Preliminary methods were
first presented to the ACIP in February 2005, when the committee
suggested that the evidence-based process be piloted on two ACIP
recommendations. Continued work reviewed and adapted the evidence-based
methods of the U.S. and Canadian Preventive Services Task Forces, the
U.S. Task Force on Community Preventive Services, and the Oxford Centre
for Evidence-Based Medicine.

ACIP vaccination recommendations are unique in their two major
components, value to individuals and to community health. Although not
every recommendation has community health implications (e.g., no
transmissibility), both need to be clear when they are present. The
pilot project has helped develop a method useful to modify the
recommendations to five analytical steps for the ACIP process:

1.  *Develop an analytic framework.* An analytic framework was outlined
    for the committee. Its steps were similar for both individual and
    public health, addressing vaccine usefulness, safety, effectiveness
    and efficaciousness, economic implications, and other vaccination
    considerations of an ACIP recommendation. For communities, the
    framework considers whether vaccinating a large number of
    individuals prevents transmission. The rabies vaccine recommendation
    was used as an example of one of a few recommendations that need not
    be evidence based. There are no non-ACIP dosage regimens and it is
    administered intradermally. That is not approved in the U.S., but
    the vaccine saves lives worldwide. The statement would have two
    components: prophylaxis with rabies vaccine for pre- and
    post-exposure, with five doses of vaccine and human rabies immune
    globulin in addition to wound cleansing.

2.  *Search for and collect the evidence*. The Working Group is
    searching for and collecting evidence through MEDLINE and the
    Cochrane library, bibliographies of relevant studies, and
    consultation with subject matter experts to find older or
    unpublished literature. Additional searches, data sources (e.g.,
    VAERS) , or inclusion criteria are being specified by each vaccine
    working group. For rabies, a single study was found that used the
    ACIP-approved regimen, but for a vaccine no longer licensed in the
    U.S. (Wyeth's human diploid cell rabies vaccine). They included
    studies of other biologics not currently U.S.-licensed to gather
    efficacy and effectiveness data as an evidence base for rabies
    treatment. The data scarcity forced the use of data on intermediate
    (elicit an antibody response) as well as final health outcomes.

3.  E*valuate the quality of the evidence.* A level of evidence is being
    assigned based on the design of the study reviewed. The quality of
    study execution is assessed by examining six categories of potential
    threats to internal validity: the population and intervention
    description; the sampling done; exposure and outcome measurements;
    the data analysis; the interpretation of results; and others. A
    rating of "good" involves no or one study limitation; "fair"
    involves 2-4 limitations and "limited" involves more than 5
    limitations. For rabies, a postexposure table was provided as an
    example, for the simple rabies nerve-tissue brain vaccine and for
    the human diploid cell vaccine. Determining the quality of the
    evidence and the magnitude of the effect was the most challenging
    aspect of the exercise, and the ACIP's input was requested. The
    absence of community data was clearly represented by the one-armed
    (individual health effect) analytic framework for rabies
    vaccination. Additionally, there are almost no related economic data
    with which to calculate the cost effectiveness for the ACIP's
    postexposure treatment advice. The Working Group is developing CE
    models for common scenarios faced by clinicians, with the help of
    Dr. Martin Meltzer, and a model will be created to calculate the
    benefit of the annual investment in rabies postexposure prophylaxis,
    despite multiple unknowns.

4\. *Summarize the evidence*. The evidence is summarized on separate
tables for each key aspect of efficacy and effectiveness, safety, and
economics. The quality of the aggregate evidence is determined by
looking at (1) design hierarchy and (2) quality of execution for all
studies together. Finally the magnitude of effect is established by the
combined outcomes and effect measures for all the reviewed studies.

5.  *Convert the evidence into an overall recommendatio*n. The Working
    Group plans to use four evidence groupings: 1) Immunization is not
    recommended for the target group; 2) consider individually
    recommendation; 3) immunization is not recommended for the target
    group; and 4) evidence is insufficient to make an overall
    recommendation.

Several points in this process prompted vigorous discussion:

-   Again, for rabies: although pre-exposure prophylaxis is critical in
    the animal kingdom, it has little application for humans, and the
    human treatment has virtually no community health component. And the
    question became, with no final health-outcome studies using the
    ACIP-approved vaccine regimen, on what evidence basis can the ACIP
    vote?

-   One considerations debated by the Working Group was whether
    vaccination should be provided for free, which studies show improve
    uptake.

-   Implementation of recommendations is already known to be difficult
    outside of the routine childhood vaccination schedule. Should the
    ability to implement be a consideration? Also in terms of
    implementation, what can a busy clinician do? They are already too
    busy to implement even a fraction of the most strongly recommended
    preventive services.

-   How are off-label recommendations to be handled in an evidence-based
    protocol (e.g., an ACIP recommendation for a narrower range of a
    target population)? Fitting that into the model is not easy, nor is
    the fit of permissive language.

*Next steps:* The methods paper will be completed and presented at the
June ACIP; the evidence-based rabies recommendation will be presented in
June or October, and then followed by the evidence-based zoster
recommendation.

*Discussion* included:

-   Dr. Marcuse anticipated that the options (recommend; option; do not
    recommend; or no evidence base to be used) will ultimately require
    stratification as well. For example, would universal influenza
    immunization have equal weight to other recommendations, such as
    hepatitis B or measles?

-   There is no set formula being developed to go from the design
    hierarchy and the quality of execution to a letter grade. Rather,
    the Working Group expects that the working group developing a
    statement/recommendation will suggest final recommendations, but the
    decision will still rest on the ACIP's judgment.

-   Mr. Beck asked what value there is for an economic analysis that
    finds no cost effectiveness, as defined by the measures used for a
    community program. Dr. Fishbein answered that, while many
    interventions in the Community Guide may be cost saving, there are
    others that are not cost saving but are still relatively cost
    effective in terms of quality adjusted life years. He offered to
    explain this further after the meeting.

-   Dr. Martin Myers wondered how this would affect the ACIP's
    harmonized recommendations with its partner organizations. Dr.
    Marcuse found it to harmonize beautifully with the AAP's
    evidence-based system and to be easily translatable.

-   Dr. Pickering asked how this analytic framework compared or fit to
    others in use, and how well the ACIP's might be accepted by other
    organizations. Dr. Fishbein responded that the AHRQ is developing
    guidelines for the American College of Physicians to endorse the
    evidence-based recommendations of other organizations. Since the
    basis is evidence, there well could be some cross-endorsement. He
    was confident that this framework would fit the ACP's needs. He also
    shared a chart of the USPSTF grading system to show its
    compatibility with the ACIP's potential new system:

USPSTF

A- Intervention strongly recommended

B-Intervention recommended

C- No recommendation for or against intervention

D- Intervention not routinely recommended

I- Evidence insufficient to recommend for or against.

ACIP?

A- Immunization recommended

B- Immunization recommended

C-Consider individually

D-Immunization not recommended

I- Evidence insufficient to make an overall recommendation

-   Dr. Martin Myers

-   wondered how this would affect the ACIP's harmonized recommendations
    with its partner organizations. Dr. Marcuse found it to harmonize
    beautifully with the AAP's evidence-based system and to be easily
    translatable.

    **Closing comments.**

With Dr. Abramson's thanks and no further comment, the meeting was
adjourned at 4:03 p.m.

**I hereby confirm that these minutes are accurate to the best of my
knowledge.**

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

Jon Abramson, MD, Chair

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

Date

Attachment : Attendance

Name /Organization

Dr. Shefer Abigail - Centers for Disease Control and Prevention

Jon S. Abramson MD - Wake Forest University School of Medicine

Kanowitz Adam - Families Fighting Flu

Samuels Alicia MPH - American Cancer Society

Rue Alison - Centers for Disease Control and Prevention

Kanowitz Alissa - Families Fighting Flu

Dr. Thierry Allavoine - Sanofi Pasteur Msd

Jennifer Allen - Merck & Co., Inc.

Ms. Friedman Allison MS - Centers for Disease Control & Prevention

Dr. Kempe Allison MD, MPH - University of Colorado Health Sciences
Center

Ban Mishu Allos - Vanderbilt University

Norma Allred - CDCP NIP

Dr. Bandell Allyn Pharm.D. - Medimmune

Dr. Cohn Amanda - National Immunization Program

Mrs. Welsh Amanda - GlaxoSmithKline

Miss Whatley Amanda MPH -Centers for Disease Control and Prevention

(Division of Global Migration and Quarantine)

Togba Amelia -Personal

Ms. Parker Amy MSN, MPH - Centers for Disease Control and Prevention

Pollack Amy E. MD, MPH - Columbia University

Dr. Chevez Ana MD MPH - Emory University

Dr. Chevez Ana E MD, MPH - Emory University

Dr. Dayton Ana E. MD - Constella Group

Mr. Padmanabhan Anant - SG Cowen

Dr. Calugar Angela MD, MPH - NIP/CDC

Ms. Makepeace Angelica RN, BSN - St. Joseph\'\'s Hospital of Atlanta

Ms. Isenhower Anne - American Cancer Society

Dr. Schuchat Anne MD - Centers for Disease Control and Prevention

Paula W. Annunziato M.D. - Merck & Co., Inc.

Dr. Mounts Anthony M.D. - Centers for Disease Control and Prevention

Mr. Wisniewski Anthony - MedImmune, Inc.

William Atkinson - National Immunization Program, CDC

James M Baggs - Centers for Disease Control and Prevention

Carol J. Baker - American Academy of Pediatrics

Dr. Jiang Baoming PhD - CDC

Ms. Bardenheier Barbara MPH, MA - CDC

Eliav Barr M.D. - Merck Research Laboratories, Merck & Co., Inc.

Michelle Basket - CDC

Dr. De Vos Beatrice MD - GlaxoSmithKline Biologicals

Robert L. Beck - Robert L. Beck: ACIP Voting Member

Sloat Ben MPH - Georgia Division of Public Health

Dr. Schwartz Benjamin - National Vaccine Program Office

Joan Benson MD, MPH - Merck & Co., Inc.

Stuart Berman - Centers for Disease Control and Prevention

Stevenson Beth MPH - Centers for Disease Control and Prevention

Anderson Bethany - National Immunization Program, CDC

Pollard Bette - Centers for Disease Control and Prevention

Achal Bhatt - CDC/NIP/ISD

Dr. Phelps Bill PhD - American Cancer Society

Kaafee Billah - MedImmune, Inc.

Gostout Bobbie MD - Society of Gynecologic Oncologists

Andrew Bowser - AB Writing and Editing, Inc. (media)

Damian Braga - sanofi pasteur

Teresa Lynnette Brammer - Centers for Disease Control and Prevention

Camp Brendan - Centers for Disease Control and Prevention

Rutland Brent - sanofi pasteur

Joseph Bresee - Influenza Branch, CDC

Mr. Katzowitz Brian - Children\'\'s Healthcare of Atlanta

Dr. McAlvin Brian MD - Emory University

Edward W Brink - CDC/National Immunization Program/Program Operations
Branch

Karen R. Broder - National Immunization Program, CDC

Dennis Albert Brooks - Merck & Co., Inc

Kristin Brown - CDC-NIP (contractor through SAIC)

Dr. Gellin Bruce MD, MPH - Department of Health and Human Services

Judith R. Campbell M.D. - Advisory Committee on Immunization Practices

Scott Campbell - CDC

Doug Campos-Outcalt - American Academy of Family Physicians

Maria Victoria Cano - Centers for Disease Control and Prevention

Mr. Garcia-Tunon Carlos - Morgan Stanley

Ms. Henderson Caroline - Emory University

Dr. Bridges Carolyn MD - CDC

Dr. Deal Carolyn - National Institutes of Allergy and Infectious
Diseases, NIH

Dr. Runowicz Carolyn MD - University of Connecticut Health Center

Christine Casey - Centers for Disease Control and Prevents

Dr. Hanlon Cathleen VMD - CDC

Rupprecht charles - Cdc

Thompson Charlis - CDC/NIP

James E. Cheek - Indian Health Service

Ana Elena Chevez - Emory University

Bo-Hyun Cho - National Immunization Program

Dr. Coffey Chris MD - Ross Clinic

Dr. Shibutani Chris MD - JPMorgan - Healthcare Research

Gause Christine PhD - Merck & Co., Inc.

Miss Stephen Clarencia - MedImmune, Inc.

Vellozzi claudia md, mph - cdc/nip

Dr. Lewin Clement - Acambis

Stephen L. Cochi - Centers for Disease Control and Prevention

Kathleen Coelingh - MedImmune Vaccines

Dr. curtis colette M.D.- Emory University Hospital

Estivariz Concepcion MD - National Immunization Program,

Centers for Disease Control and Prevention

Lenore Cooney - Cooney Waters

Nancy J. Cox - Centers for Disease Control and Prevention

Mr. Heit Craig - Cooney/Waters Group

Suhr Cristen MPH - Centers for Disease Control (Contractor)

George Tams Curlin - National Institutes of Health

Dr. Jorgensen Cynthia DrPH - CDC

Miss Knighton Cynthia - Centers for Disesase Control and Prevention

Mr. Babcock Dale - National Immunization Program

Dr. Morse Dale MD, MS - New York State Department of Health

Dr. Guris Dalya MD, MPH - CDC

Mr. Braga Damian - Sanofi pasteur

Dr. Gordon Daniel MD - Sanofi Pasteur Inc

Dr. Payne Daniel PhD - Centers for Disease Control

Natalie J. Darling - CDC

Dr. Salisbury David CB - Department of Health

Dr. Schofield David Pharm D - GlaxoSmithKline

Jill Davila - CDC -- LHI

Xiaohong Davis - CDC/DVRD/Influenza

Anna DeBlois - Association of State and Territorial Health Officials

Shelley Deeks - Public Health Agency of Canada

Dr. Kruzikas Denise PhD - GlaxoSmithKline

Penelope H. Dennehy M.D. - American Academy of Pediatrics

Ms. Gaffoglio Diane - Nancy Lee & Associates

Dr. Simpson Diane MD, PhD - National Immunization Program

Dr. CAMPENS Dirk - GLAXOSMITHKLINE BIOLOGICALS

Mr. Dalrymple Donald \"Dack\" - Dalrymple & Associates, LLC

Humphrey-Franklin Donelle - Public Health

Dr. Rickert Donna DrPH - Centers for Disease Control

Jag Dosanjh - GlaxoSmithKline

Mr. Kilgus Duane - Centers for Disease Control and Prevention

Gary Dubin - GlaxoSmithKline Biologicals

Eileen Dunne - CDC

Mr. Gwozda Ed - GlaxoSmithKline

Reed Eddie MD - DCPC, NCCDPHP, CoCHP, CDC

Dr. Yamada Eileen - Immunization Branch, California Department of Health
Services

Dr. Perry Elaine MD - Merck and Co., Inc.

Elbasha Elamin - Merck & Co., Inc

Goss Elizabeth - Ropes & Gray

Unger Elizabeth PhD, MD - Centers for Disease Control and Prevention

Mr. Weintraub Eric - CDC/OCSO/ISO

Dasbach Erik PhD - Merck Research Laboratories

Grau Erik - sanofi pasteur

Burns Erin - Influenza Branch, Centers for Disease Control and
Prevention

Ms. Joseph Eugenia - Parents

Gary L. Euler - Centers for Disease Control and Prevention

Geoffrey Evans M.D. - National Vaccine Injury Compensation Program,

Health Resources and Services Administration

James Everette Evans - Sound On-Site, Inc.

Dr. Soud Fatma PhD, RN - Immunization Safety Office

Mark B. Feinberg MD, PhD - Merck & Co., Inc.

Mr. Han Feng - Henry Schein, Inc

Reginald Finger - ACIP member (no affiliation)

Daniel B. Fishbein - CDC

Amanda Foley - GlaxoSmithKline

Stephen M. Ford - Military Vaccine Agency

Stephan L Foster Pharm.D.- ACIP Liaison Representative - APhA

Dr. Lebel Francois - MedImmune Inc.

Dr. Malinoski Frank - MedImmune, Inc.

Dr. Clark Fred PhD - The Children\'\'s Hospital of Philadelphia

Mr. Wyand Fred - American Social Health Association

Leonard R Friedland - GlaxoSmithKline

Miss Sylvina Frutos - GlaxoSmithKline

Jeffrey Fu PhD - Merck & Co., Inc.

Dr. Xu Fujie MD, PhD - Centers for Disease Control and Prevention

Stanley A. Gall M.D. - The American College of Obstetricians and
Gynecologists

Sandra Gambescia - Centers for Disease Control and Prevention

Demetria Gardner - Centers for Disease Control and Prevention

Paul M. Gargiullo - Centers for Disease Control and Prevention; National
Immunization Program; Epidemiology and Surv eillance Division

Mr. Stein Gary - Families Fighting Flu

Diana Gaskins BSN, MSN - Division of Public Health, Georgia Immunization
Program

Mr. Porges Geoff PhD - Sanford C. Bernstein

Dr. Garnett Geoffrey PhD -Imperial College London

Dr. Porges Geoffrey - Sanford Bernstein

Jeff George M.D. - New York,

Jeffrey George - TDG Inc.

Peter Georges MD - Brown Medical School

Ruth Gilmore - Georgia Immunization Program

Janet R. Gilsdorf - University of Michigan

Dr. Mootrey Gina DO, MPH - Centers for Disease Control and Prevention

Roger Glass - CDC

John W. Glasser - Centers for Disease Control and Prevention

JIll Gordon-Evans - Sound On-Site, Inc.

Michelle G. Goveia - Merck Research Laboratories, Merck & Co., Inc.

Jesse Earl Greene - South Carolina Department of Health and
Environmental Control

Amy Groom - Indian Health Service

Dr. Herrera Guillermo MD, MBA - CDC

Jill G. Hackell - Wyeth

Neal Arthur Halsey - Johns Hopkins University

Danielle Halstrom - GlaxoSmithKline

Claire Hannan - Association of Immunization Managers

Mr. Chesson Harrell PhD - Centers for Disease Control and Prevention

Dr. Strothers Harry MD, MMM - Morehouse School of Medicine

Richard M. Haupt M.D. - Merck & Co., Inc.

Penny M. Heaton - Merck Research Laboratories

Dr. Baggett Henry MD, MPH -Centers for Disease Control and Prevention

Teresa M. Hesley - Merck & Co., Inc.

Beth F. Hibbs - CDC OD OSCO ISO

Mark Hirth - Merck & Co., Inc

Barbara J Howe - GlaxoSmithKline

Dr. BOGAERTS Hugues - GLAXOSMITHKLINE BIOLOGICALS

Dr. Harry Hull - Minnesota Department of Health

Harry Frazer Hull - Minnesota Department of Health (member ACIP)

Gina Hunt - Merck & Co., Inc.

Dr. Jevaji Indira MD - Health Resourses and Services Adminstration

Bruce L. Innis M.D - GlaxoSmithKline

Dr. Chan Ivan - Merck Research Labs

Dr. Alexander James Jr.- CDC

Kelly James - Goldman Sachs

Dr. Pellissier James - Merck Research Laboratories

Ransom James - NACCHO

Mr. Singleton James - National Immunization Program, CDC

Mr. Harrison James R. MAPA- CDC/CCID/National Immunization Program

Ms. Agosti Jan MD - Bill & Melinda Gates Foundation

Dr. Gidudu-Nsubuga Jane MD,MPH - Immunization Safety Office, Office of
the Chief Science Officer,CDC

Ms. Quinn Jane - GlaxoSmithKline

Dr. Seward Jane MBBS, MPH - CDC

Dr. Zucker Jane MD, MSc- New York City Department of Health and Mental
Hygiene

Ms. Skidmore Janet - Merck & Co., Inc.

Shirley Jankelevich - South Carolina Department of Health and
Environmental Service

Dr. Hong Jason PhD- Sanford C. Bernstein

Mr. Schwartz Jason MBE - University of Pennsylvania Center for Bioethics

Bauman Jay - MedImmune, Inc.

Mr. Hackman Jeff - MedImmune, Inc.

Dr. Chodakewitz Jeffrey MD - Merck & Co.

Dr. Cooper Jeffrey MD - Cooper Pediatrics, PC

Dr. Duchin Jeffrey MD - Public Health Seattle & King County

Dr. Silber Jeffrey - Merck & Co., Inc.

Mr. Stoddard Jeffrey MD - MedImmune, Inc.

Ms. Huntington Jennifer - Emergent BioSolutions

Mrs. Lastinger Jennifer - Families Fighting Flu

Tai Jennifer MD - Vanderbilt University School of Medicine

Ms. White Jennifer - Ketchum

Ms. Zavolinsky Jennifer MHS, CHES -Every Child By Two

Mr. Shelton Jerry RPh - Merck Vaccine Division

Mr. Blanton Jesse MPH - Centers for Disease Control and Prevention

Ms. Leung Jessica - National Immunization Program

Ms. Xi Jian - GlaxoSmithKline

Hackell Jill MD - Wyeth Vaccines Research

Dr. Buffington Joanna - Centers for Disease Control and Prevention

Kearney Joanne - Solvay Pharmaceuticals

Mr. Lastinger Joe - Families Fighting Flu

Dr. Modlin John MD - Dartmouth Medical School

Mr. Vittas John - Families Fighting Flu, Inc.

Dr. Douglas, Jr. John M. MD - Centers for Disease Control and
Prevention, National Center of HIV, STD & TB Prevention, Divison of STD
Prevention

David Rue Johnson MD, MPH - sanofi pasteur

Tanya A. Johnson - Oak Ridge Institute for Science and Technology
(ORISE)/CDC/National Immunization Program (NIP)

Mary Suzanne Johnson-DeLeon - Centers for Disease Control and Prevention

Dr. Bocchini, Jr. Joseph M.D. - American Academy of Pediatrics

Dr. Heyse Joseph - Merck Research Laboratories

Mr. Sullivan Joseph - Merck & Company, Inc.

M. Patricia Joyce M.D.- Centers for Disease Control

Mrs. Magner Judith - GlaxoSmithKline Pharmaceuticals

Miss Rusk Judith - Infectious Diseases in Children and Infectious
Disease News

Dr. Shindman Judith - sanofi pasteur Limited

Dr. Schmidt Judy EdD - CDC NIP EIPB

Ms. Gee Julianne - Centers for Disease Control and Prevention

Ms. Schafer Julie MPH, MS - Office of the Secretary, Department of
Health and Human Services

Laurie Kamimoto - CDC

Ms. Mason Karen MPA - National Immunization Program

Mrs. Townsend Karen RN - Georgia Chapter American Academy of Pediatrics

Ms. Sapsis Kari MPH - National Immunization Program-CDC

Mr. Iqbal Kashif - NIP/CDC

Dr. Poehling Katherine MD, MPH - Vanderbilt University Medical Center

Dr. Neuzil Kathleen MD,MPH - PATH

Ms. Harbour (Felton) Kathryn - Centers for Disease Control and
Prevention

Dr. Kohl Katrin MD, PhD, MPH- Centers for Disease Control and Prevention

Mark Katz - Centers for Disease Control and Prevention

Samuel Lawrence Katz -Infectious Diseases Society of America

Mrs. Dougherty Kelley - Merck & Co., Inc.

Ms. Green Kahn Kelly MPA - American Cancer Society

Conzen Kendra - CDC Div Global Migration and Quarantine

Mr. Bart Kenneth MD, MPH, MSHPM -Department of Health and Human
Services, National Vaccine Program Office

Mr. Dennison Kenneth - Wyeth Pharmaceuticals

Dr. Schmader Kenneth - Duke University/Durham VA Medical Centers

Dr. Ault Kevin MD - Emory University School of Medicine

Dr. Hazelwood Kimberley Pharm D - Public Heatlh

Dr. workowski kimberly md - centers for disease control and prevention

Maureen Kolasa - Centers for Disease Control

Katrina Kretsinger - National Immunization Program, CDC

Armendariz Kris - Society of Gynecologic Oncologists

Mrs. Charlotte Kroft - GlaxoSmithKline

Barbara J. Kuter Ph.D., MPH - Merck & Co., Inc.

Dr. Anderson Larry MD - DVRD, NCID, CDC

Philip S. LaRussa - Columbia University

Ms. Leidel Laura - Centers for Disease Control and Prevention/Office of
Director/Immunization Safety Office

Miss Richardson Laura - Influenza Branch-CDC

Mrs. Johnson Laurie - Centers for Disease Control and Prevention

Len Lavenda - sanofi pasteur

Herschel W. Lawson - Centers for Disease Control and Prevention

Charles W. LeBaron - NIP

Dr. Bennett LEE - SANOFI PASTEUR MSD

Marie-Michele Leger - American Academy of Physician Assistants

Laura Leidel - Centers for Disease Control and Prevention

Ms. Cooney Lenore C - Cooney/Waters Group

Roland A. Levandowski M.D. - National Institutes of Health

Tracy Lieu - Harvard Pilgrim Health Care and Harvard Medical School

Anna M. Likos - Centers for Disease Control and Prevention

Dr. Alexander Linda PhD - Digene Corporation

Ms. Russell Lola - CDC, OD Media Relations

Mr. Thomas Lonnie - Henry Schein Incorporated

Adriana Lopez MHS - Centers for Disease Control and Prevention

Dr. Gavin Loretta MPH, PhD - Division of Reproductive Health, CDC

Suchita A. Lorick - CDC/NIP/ISD

Douglas R. Lowy M.D - National Cancer Institute, National Institutes of
Health

Beverly J. Lybrand - Merck & Company, Inc.

Ms. Bahta Lynn RN - Minnesota Department of Health

McIntyre Lynne - Centers for Disease Control and Prevention

Dr. Otten Mac MD - CDC, NIP

Andrew Macknight - GlaxoSmithKline

Susan Patricia Malone - Coastal Health District 9-1

Dr. Patel Manisha MD - Centers for Disease Control and Prevention

Susan E. Manning - CDC

Edgar K. Marcuse MD, MPH - Children\'\'s Hospital and Regional Medical
Center

Cortese Margaret - CDC

Ms. McGlynn Margaret - Merck & Co., Inc.

Watkins Margaret - CDC

Ms. Murray Marie - SoWrite

Lauri Markowitz - Centers for Disease Control and Prevention

Tanner Wilson Marsha - Society of Gynecologic Oncologists

Ms. Doroshenk Mary MA - American Cancer Society

Mrs. Eiken Mary - Society of Gynecologic Oncologists

Ms. Mulholland Mary - National Immunization Program

Dr. Staat Mary M.D., MPH - Associate Professor of Pediatrics, Cincinnati
Children\'\'s Hospital Medical Cente

Dr. Lindegren Mary Lou MD - CDC

Christopher Mast - Merck Research Laboratories

Eric Edward Mast - Centers for Disease Control and Prevention

Dr. Esona Mathew Ph.D - CCID/Centers for Disease Control and Prevention

Mr. Garrett Matt - Wyeth Vaccines

Mr. David Matthew MD - Independent

Hogben Matthew PhD - Centers for Disease Control and Prevention

Dr. Ciarlet Max - Merck & Co., Inc.

Dr. El Sherif May MD - Centers for Disease Control and Prevention

Mary McCauley - National Immunization Program

William Paul McKinney - University of Louisville School of Public Health
and Information Sciences

Lindley Megan MPH - National Immunization Program/ Centers for Disease
Control & Prevention

Wharton Melinda - National Immunization Program, CDC

Ms. Arvay Melissa - CDC

Miss Habel Melissa - CDC, Division of STDP, BIRB

Lynne Mercedes - Georgia Division of Public Health

Dr. Decker Michael - sanofi pasteur

McNeil Michael MD - CDC

Dr. Pride Michael PhD - Wyeth Research

Tidwell Michelle RN, BSN - Georgia Chapter American Academy of
Pediatrics

Amy B. Middleman MD, MPH, MS Ed - Baylor College of Medicine

Christina M. Mijalski - Centers for Disease Control, National
Immunization Program

Elaine R. Miller - Centers for Disease Control and Prevention (CDC)

Tucker Miriam E. - Pediatric News

Ann Moen - Centers for Disease Control

Ms. Gaul Moira MPH - Family Research Council

Dr. Marin Mona MD - CDC

Dr. Saraiya Mona MD, MPH - CDC

Martha C. Monroe - Centers for Disease Control

Kelly Lynn Moore MD, MPH - Tennessee Department of Health

John S. Moran - Centers for Disease Control and Prevention

Julie Morita - Chicago Department of Public Health

Dale Morsr M.D. - New York State Department of Health

Linda S. Murphy - Centers for Medicare & Medicaid Services

Trudy Murphy - Centers for Disease Control and Prevention

Martin G. Myers - National Network for Immmunization Information

Dr. Cox Nancy PhD - Centers for Disease Control and Prevention

Ms. Fasano Nancy - National Immunization Program CDC

Ms. Roach Nancy - n/a

Mrs. Stoback Nanette - sanofi pasteur

Ms. Revzina Natalya MD - Centers for Disease Control and Prevention

Dr. Monika Naus - on behalf of Public Health Agency of Canada; British
Columbia Centre for Disease Control

Mr. Agran Neal - Sanford Bernstein

Deb Neivert - MedImmune

Thomas M. Netzer - Merck & Co., Inc.

Kristin Lee Nichol Department of Veterans Affairs Medical Center

Dr. Liddon Nicole - Centers for Disease Control and Prevention

Karen H Nielsen - GlaxoSmithKline

Ms. Dahill Noreen - GlaxoSmithKline

Dr. Baylor Norman Ph.D. - Food and Drug Administration

Glen Nowak - Centers for Disease Control and Prevention

Dennis J. O\'\'Mara - Immunization Services Division, National
Immunization Program, CDC

M. Carolyn O\'\'Mara - Centers for Disease Control and Prevention,
Health Marketing, Creative Services

Paul Allan Offit MD - The Children\'\'s Hospital of Philadelphia

Peter R. Paradiso - Wyeth

Umesh Parashar - CDC

Smith Parker - Parker Smith Photography

Mr. BAROLLIER Pascal - GlaxoSmithKline

Wortley Pascale - CDC

Manisha Patel - CDC, NIP

Dr. Offit Paul MD - The Children\'\'s Hospital of Philadelphia

Mrs. Rose Paula - GlaxoSmithKline Pharmaceuticals

Christine Pearson - Centers for Disease Control and Prevention

Michele Pearson - Centers for Disease Control and Prevention

Dr. Nuorti Pekka MD, DSc - Centers for Disease Control and Prevention

Haber Penina MPH - CDC

Mrs. Heaton Penny MD - Merck & Co., Inc.

Mr. Sprigg Peter - Family Research Council

Diane C. Peterson - Immunization Action Coalition

Mr. Hosbach Philip - sanofi pasteur

Dr. MONTEYNE Philippe MD, PhD - GlaxoSmithKline Biologicals S.A.

Ms. Arthur Phyllis - Merck & Co Inc

Larry K. Pickering - Centers for Disease Control and Prevention

Cheng Po-Yung Ph.D. - CDC/NCID/DVRD/I/ES

Gregory A. Poland - Mayo Clinic and Foundation

Alicia Postema - CDC/CCID/NCID/DVRD/Influenza

Keith R. Powell - American Academy of Pediatrics, Committee on
Infectious Diseases

Dr. Kutty Preeta MD, MPH - Centers for Disease Control and Prevention

Dr. Eidex Rachel PhD - Centers for Disease Control and Prevention

Mrs. Hlay Rachel - GlaxoSmithKline

Aaron Thomas Rak - CDC, NIP, ISD

Dr. Strikas Raymond M.D. - National Immunization Program

Ms. Werth Rebecca - GlaxoSmithKline

Dr. Turcios Reina - Centers for Disease Control and Prevention

Dr. Jenkins Renee R. MD - Howard University

Margaret Rennels - GlaxoSmithKline

Margaret B Rennels - GlaxoSmithKline

Mr. Dinovitz Richard - Wyeth Pharmaceuticals

Dr. Dixon Richard M.D. - Centers for Disease Control and Prevention;
NCHM; DPPP

Dr. Franka Richard PhD. - Centers for Disease Control and Prevention

Kanowitz Richard - Families Fighting Flu

Dr. Salmon Richard DO - Children\'\'s Healthcare of Atlanta at Scottish
Rite

Mr. Nelson Rick - National Immunization Program/CDC

Donna Rickert - Centers for Disease Control and Prevention

Dr. Helfand Rita - CDC

Dr. Itzler Robbin PhD - Merck Research Laboratories

Mr. Morlend Robert - Centers for Disease Control

Mr. Oliver Robert - Wyeth Pharmaceuticals

Perry Robert M.D. - Centers for Disease Control and Prevention

Dr. Steinbrook Robert M.D. - New England Journal of Medicine

Mr. Cuca Roberto - JP Morgan

Dr. Womeodu Robin MD - Methodist University Hospital

Lance E. Rodewald M.D. - National Immunization Program, CDC

Von Roebuck - Centers for Disease Control and Prevention

Dr. bernier roger phd - nip

Dr. Levandowski Roland MD - National Insitutes of Health, National
Insititue of Allergy and Infectious Diseases

Dr. Rodriguez Romeo - CENSIA (SS)

Mr. Hibshoosh Ron - Goldman Sachs JBWere

Mr. Van Duyne Ron - Immunization Information Systems, NIP, CDC

Ms. Dhara Rosaline MA.,MPH - CDC

Dr. Tiernan Rosemary MD, MPH - Division of Vaccines, Center for
Biologics, FDA

Sandra W. Roush - CDC/NIP/ESD

Beth Rowe-West - DPH-DHHS-NC Immunization Branch

Dr. Patricia Saddier MD, PhD - Merck Research Laboratories

Turner Sam - Ropes & Gray

Dr. Katz Samuel MD - Duke University Medical Center

Dr. Dos Santos Chaves Sandra MD - Centers for Disease Control and
Prevention

Tammy A. Santibanez - National Immunization Program

Dr. Jeanne M. Santoli MD, MPH - CDC NIP

Ms. Landry Sarah - GlaxoSmithKline

Ms. Spurgeon Sarah - New England Healthcare Institute

Mona Saraiya - CDC

Debbie Saslow PhD - American Cancer Society

Carlos Sattler M.D. - Merck & Co., Inc.

William Schaffner MD - Chairman, Department of Preventive Medicine,
Vanderbilt University School of Medicine

Florian Schodel M.D - Merck Research Laboratories

Anne Schuchat - Centers for Disease Control and Prevention

Dr. Schmid Scott PhD - Centers for Disease Control and Prevention

Ms. Shapowal Sharon - GlaxoSmithKline Pharmaceuticals

Kate M. Shaw - CDC

David K Shay - CDC

Dr. Leader Shelah PhD - Medimmune

Tom Shimabukuro - CDC/NIP

Alan J. Sievert M.D., M.P.H. - American Academy of Pediatrics-Georgia
Chapter

Dr. Staprans Silvija PhD - Emory University Vaccine Center

Thomas W. Skinner - CDC

Eric T. Skjeveland - Merck Vaccine Division

Barbara A. Slade M.D. - Centers for Disease Control

Ianthia Smith - Kaiser Permanente

Dr. Jean Clare Smith - Medical Officer, Assistant to the Director for
Immunization Policy, NIP, CDC

Nicole Michelle Smith - Centers for Disease Control and
Prevention/Influenza Branch

Pamela Srivastava - Centers for Disease Control

Ms. Hoffman Stacey - Centers for Disease Control

Dr. Plotkin Stanley MD - Sanofi Pasteur

Ms. Steele Stefanie - CDC

Renna Stephanie - National Immunization Program

Dr. Cochi Stephen MD - Centers for Disease Control and Prevention

Mr. Yoo Steve - Sanford Bernstein

Dr. Gordon Steven MD - Cleveland Clinic Foundation

Dr. Rosenthal Steven MD - FDA/CBER

Mr. Vignau Steven - Merck & Co., Inc.

Patricia (Patsy) Stinchfield CPNP - Children\'\'s Hospitals and Clinics
of Minnesota

Shannon Stokley - Centers for Disease Control and Prevention

Raymond A. Strikas M.D. - CDC NIP

Stacy Stuerke - Merck Vaccine Division

Mrs. Crosby Susan - Women In Government

Ms. Garfield Susan - Digene Corporation

Dr. Lett Susan MD - MA Dept Public Health

Dr. Reef Susan MD - CDC, NIP

Ms. Van Aacken Susan - National Immunization Program

Ms. Watkins Susan - Sanofi pasteur

Ms. Matter Susanna - Leerink Swann

Ms. LAW Suzette - Centers for Disease Control and Prevention

Dr. Gregg Sylvester - Merck & Co., Inc.

Litjen (L.J) Tan - American Medical Association

Ms. Malik Tasneem - CDC/National Immunization Program

Jonathan L. Temte MD/PhD - American Academy of Family Physicians

Ms. Rutledge Teresa BA - Centers for Disease Control and Prevention

Andrew Kroger Thaddeus - Centers for Disease Control and Prevention

Dr. Allavoine Thierry - SANOFI PASTEUR MSD

Dr. Uyeki Tim MD, MPH, MPP - Centers for Disease Control and Prevention

Mr. Wang Tim - UBS Securities

Mr. Obara Timothy - GlaxoSmithKline

Tejpratap S. P. Tiwari MD - Centers for Disease Control and Prevention

Dr. Shimabukuro Tom MD, MPH, MBA - CDC/NIP

John Treanor - University of Rochester

Monica Trigg - Georgia Immunization Program

Ms. Watson Tureka L. - McKing Consulting Corporation

James C. Turner MD - American College Health Association

James P. Tursi M.D. - GSK Biologicals

Mr. Jodhpurkar Uday - Sanofipasteur

Elizabeth R. Unger - Centers for Disease Control and Prevention

Thomas M. Vernon MD - Consultant to Vaccine Companies

Dr. Benard Vicki - CDC

Peter Vigliarolo - Cooney Waters Group

Mr. Ahonkhai Vincent M.D. - GlaxoSmithKline Pharmaceuticals

Charles Vitek - CDC (National Center for HIV, STD, and TB Prevention)

Cara Vivarelli-O\'\'Neill - Merck & Co., Inc

Mr. Garrett W. Matthew - Wyeth

Gregory S. Wallace - Centers for Disease Control and Prevention

Teresa R. Wallis - Centers for Disease Control and Prevention

Dr. Orenstein Walter MD - Emory University

Elisabeth A. Ward - Georgia Division of Public Health

Barbara May Watson - Division of Disease Control, Immunization Program,
The Philadelphia Department of Public Health

Dr. Hachey Wayne DO, MPH - Department of Defense

Donna L. Weaver - National Immunization Program, CDC

David Webster - Webster Consulting Group

Bruce G. Weniger MD - CDC

Deborah L. Wexler MD - Immunization Action Coalition

Mark Alan Whitaker M.D. -America\'\'s Health Plans

Marc -Alain Widdowson - Centers for Disease Control and Prevention

Eddie L. Wilder - CDC, NID, ISD

Dr. Thompson William PhD - OCSO/Immunization Safety Office

Dr. Vecino William MD - MKGNY

Amy Wishner - PA Chapter, American Academy of Pediatrics

Charles (Skip) Wolfe - National Immunization Program

Eileen L Yee (Lau) - Centers for Disease Control and Prevention

Elizabeth York - GlaxoSmithKline

Laura Jean York - Wyeth

Dr. Moore Zack MD - Emory University

John M. Zahradnik - sanofi pasteur

Fangjun Zhou - NIP