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DEPARTMENT OF HEALTH AND HUMAN SERVICES
CENTERS FOR DISEASE CONTROL AND PREVENTION
(CDC logo image)
Advisory Committee on Immunization Practices
June 27-28, 2007
Record of the Proceedings
Day 1, June 27, 2007
WELCOME AND INTRODUCTION
HEPATITIS A VACCINE
Introduction: Dr. Lieu
Travel Prophylaxis: Dr. Novak
Travel Recommendations: Dr. Novak
VFC Vote: Dr. Calugar
Underinsured Children: Dr. Lee
AMA/AAP Immunization Congress: Dr. Orenstein
NVAC Financing Working Group: Dr. Birkhead
PROPOSED REVISIONS TO THE ADULT IMMUNIZATION SCHEDULE
Introduction: Dr. Morse
Information: Dr. Mootrey
PROPOSED REVISIONS TO THE CHILDHOOD/ADOLESCENT SCHEDULE
Information: Dr. Calugar
CDC IMMUNIZATION SAFETY UPDATE
Information: Dr. Broder
HERPES ZOSTER (SHINGLES) VACCINE
Introduction: Dr. Treanor
Information: Dr. Chaves
Activities and Next Steps: Ms. Stinchfield
MENINGOCOCCAL CONJUGATE VACCINE (MCV4)
Introduction: Dr. Baker
Epidemiology: Dr. Cohn
Economic Model of Expansion: Dr. Ortega-Sanchez
Vaccine Supply, Private Sector: Mr. Hosbach
Vaccine Supply, Public Sector: Dr. Wallace
Vaccine Safety: Dr. Iskander
New Recommendations: Dr. Cohn
ECONOMIC ANALYSES OF VACCINES
Introduction: Dr. Lieu
Discussion: Dr. Mark Messonnier
VACCINE SUPPLY AND IMPLEMENTATION
Information: Dr. Wallace
Working Group Information: Dr. Morita
VACCINES DURING PREGNANCY/BREAST-FEEDING
Introduction: Dr. Neuzil
Information: Dr. Schrag
Information: Dr. Skoff
Day 2, June 28, 2007
Introduction and Update on LAIV: Dr. Fiore
FluMist Safety Monitoring: Dr. Broder
National Influenza Vaccine Summit: Dr. Mootrey
USE OF VACCINES IN PERSON WITH HIV/AIDS
Children and Adolescents: Dr. Seward
Adults: Dr. Mootrey
UPDATE: ROTAVIRUS VACCINES
Introduction: Dr. Treanor
VAERS and VSD: Dr. Haber
Data Interpretation: Dr. Patel
RotaTeq and Kawasaki Disease: Dr. Izurieta
UPDATE: HPV VACCINES
Introduction: Dr. Gilsdorf
Safety Update: Dr. Iskander
Quadrivalent Safety Update: Dr. Dubin
Future Considerations: Dr. Markowitz
Arkansas Outbreak: Ms. Lopez
List of Participants and Attendees
List of Acronyms
DEPARTMENT OF HEALTH AND HUMAN SERVICES
CENTERS FOR DISEASE CONTROL AND PREVENTION
Advisory Committee on Immunization Practices
June 27-28, 2007
Minutes of the Meeting
The Department of Health and Human Services (HHS) and the Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases (NCIRD) convened a meeting of the Advisory Committee on Immunization Practices (ACIP). The meeting was held on June 27-28, 2007 at CDC’s Global Communications Center in Atlanta, Georgia. The list of participants is appended to the minutes as Attachment 1. [Note: the list only includes persons who introduced themselves for the record, presented, made public comments, or registered prior to the meeting.]
Day One, June 27, 2007
WELCOME AND INTRODUCTION
Dr. Abramson welcomed attendees to the June 2007 ACIP meeting. Dr. Pickering introduced several international visitors, including Dr. Christine Ding-Ping Liu, Director of the Vaccine Center for the Centers of Disease Control in Taiwan, and members of the Turkish Adult Immunization Advisory Board. In addition, he welcomed the new liaison representative from Canada's National Advisory Committee on Immunization Practices, Dr. Joanne Langley from the Division of Infectious Diseases of the Department of Pediatrics, the Canadian Center for Vaccinology at Dalhousie University in Nova Scotia, and thanked Dr. Monika Naus, who was replaced by Dr. Langley. He noted several people who could not attend the meeting, including ACIP member Dr. Robin Womeodu. Dr. Geoff Evans was not present, but Dr. Indira Jevaji took his place; Dr. Norm Baylor was not present, but Dr. Florence Houn attended on his behalf; Dr. Wayne Hatchey from the Department of Defense was represented by Dr. Ted Cieslak; and neither Dr. Paul McKinney from the Association of Teachers of Preventive Medicine nor Dr. David Salisbury from the Department of Health in London were able to attend. Finally, Dr. Pickering announced that Dr. Sam Katz had been awarded a 2007 Pollin Prize for his contributions to pediatric infectious diseases and vaccine development, particularly his role in developing the measles vaccine with Nobel laureate Dr. John Enders.
Dr. Pickering noted that the CDC web site had been revised and that the ACIP site is updated frequently with the current version of the meeting agenda, meeting minutes and presentations, ACIP recommendations and other ACIP activities (http://www.cdc.gov/vaccines/recs/acip/default.htm ).
Dr. Pickering explained that the goal in appointing members to the ACIP is to achieve the greatest level of expertise while minimizing the potential for actual or perceived conflicts of interest. To summarize conflict-of-interest provisions applicable to the ACIP, as noted in the Policies and Procedure manual, members of the ACIP agree to forgo participation in certain activities related to vaccines during their tenure on this committee. For certain other interests that potentially enhance a member's expertise while serving on the committee, CDC has issued limited conflict-of-interest waivers. Members who conduct clinical vaccine trials or serve on safety data monitoring boards may serve as consultants to present to the committee on matters related to those vaccines. However, they are prohibited from participating in the deliberations or votes of the committee on issues related to those specific vaccines. Regarding other vaccines of an affected company, a member may participate in discussions with the proviso that he or she abstains on all votes related to the vaccines of that company. ACIP members who may have a potential conflict of interest should make it known by disclosing all of their vaccine-related financial interests and work.
Dr. Abramson noted that the terms of four members, including himself, would expire on June 30th. He presented those members with a certificate of appreciation and thanked them for their many contributions to ACIP over the years. Dr. Ban Allos, Dr. Janet Gilsdorf, and Dr. John Treanor all spoke briefly about what working on the committee had meant to them.
Dr. Abramson added his appreciation of the incredible talent found among the ACIP committee members, the liaisons, and particularly the full-time CDC staff. He then pointed out some of the accomplishments he had witnessed, starting in 1999, when thimerosal was becoming an important topic and rotavirus vaccine was causing problems over the issue of intussusception. Influenza vaccine has gone to an age-based rather than a risk-based recommendation and appears to be moving toward a universal recommendation for all children, if not for adults. Progress has been made on the ACIP-HICPAC joint statement on immunization of healthcare workers, but that needs further emphasis.
In 1999 the committee voted to stop the use of rhesus rotavirus vaccine in the U.S., with the understanding that the risk-benefit ratio differed tremendously from that of developing countries. However, manufacturers developed other safer rotavirus vaccines, which will be introduced into developing countries in the next few years.
The committee approved varicella zoster recommendations that now include the use of a routine second dose and will be looking at its impact on decreasing the occurrence of varicella disease and fixing the age shift in the occurrence of the disease. The recommended use of MMRV, despite occasional vaccine shortages, will help decrease the number of injections that children need. The herpes zoster vaccine is aimed specifically at older adults and is now recommended for routine use.
The development of an adolescent platform was a major move forward, especially use of a conjugated meningococcal vaccine. Tdap was recommended for use in adolescents as well as adults and healthcare providers. The pertussis component of this combination vaccine will have more impact now that it is being used in adolescents and adults. The impact of the human papillomavirus vaccine, the first vaccine specifically created as an anticancer vaccine, will be great; the issue of how to implement it remains to be solved.
The recommendation for use of hepatitis B vaccine in adults has been expanded, and perhaps should be expanded further. The hepatitis A recommendation also has been expanded to include all children 12 months of age and older, which has already shown a marked impact due to the high-risk part of the recommendation. The committee has continued to make recommendations based on good science and the best interest of the United States, without regard to cost. However, there is much to be done in the area of vaccine financing.
Dr. Pickering thanked Dr. Abramson for all his work as chair of ACIP and as a member of the influenza work group. He praised Dr. Abramson’s intellect and insight, as well as his compassion and integrity – particularly his concern for children and adults.
Dr. Abramson asked committee members to state any conflicts of interest.
Dr. Allos: no conflicts.
Dr. Baker: no conflicts.
Mr. Beck: no conflicts.
Dr. Gilsdorf said she was an independent safety monitor on an NIH-sponsored vaccine trial for which she receives no compensation.
Dr. Hull: no conflicts.
Dr. Lett: no conflicts.
Dr. Lieu: no conflicts.
Dr. Morita: no conflicts.
Dr. Neuzil: no conflicts.
Ms. Stinchfield: no conflicts.
Dr. Treanor said he was doing clinical trials of influenza vaccines for Protein Sciences and for Merck, and had laboratory support for influenza work from GlaxoSmithKline.
Dr. Morse: no conflicts.
Dr. Abramson said he had no conflicts, but was on an NIH data safety monitoring board for the use of oseltamivir in children less than one year old.
Dr. Pickering announced that there would be four new members joining the ACIP beginning July 1st and a fifth new member would be appointed in the very near future. The new members are Dr. Lance Chilton, a pediatrician with the Young Children's Health Center and Professor of Pediatrics at the University of New Mexico in Albuquerque; Dr. Paul Cieslak, Medical Director of the Oregon Immunization Program, Oregon State Public Health Division and Clinical Assistant Professor in Public Health and Preventive Medicine and Iinfectious Diseases at the Oregon Health and Science University; Dr. Allen Craig, State Epidemiologist from the Tennessee Department of Health, trained in family medicine; and Dr. Janet Englund, Associate Professor of the Division of Pediatric Infectious Diseases at Children's Hospital, the University of Washington and Fred Hutchinson Cancer Research Center in Seattle. As of July 1st, the new ACIP Chair will be Dr. Dale Morse, who has been an ACIP member since July of 2005. Dr. Morse is Director of the Office of Science and Public Health at the New York State Health Department. He will be assisted by Dr. Carol Baker, who will serve as the Vice Chair. Dr. Baker has been an ACIP member since July of 2006 and is Professor of Pediatrics, Molecular Virology, and Microbiology at Baylor College of Medicine.
HEPATITIS A VACCINE: POSTEXPOSURE AND TRAVEL PROPHYLAXIS
Dr. Tracy Lieu, ACIP, WG Chair
Dr. Ryan Novak, CDC/NCHHSTP/DVH
Dr. Lieu began with a reminder that the ACIP had considered draft recommendations for postexposure prophylaxis for hepatitis A in February and at that time it was apparent that more clarification and discussion were needed. An ACIP hepatitis working group was formed and was able to reach consensus on the wording of the recommendations with the hepatitis group within CDC. For postexposure prophylaxis for persons 12 months to 18 years old, vaccine is preferred to immune globulin (IG). For persons 19 to 40 years old, vaccine is preferred to IG. For persons over 40 years old, IG is preferred although vaccine can be used if IG cannot be obtained. Lastly, for patients with chronic liver disease, those who are immunocompromised, and children less than 12 months old, IG should be used.
These recommendations also affect the recommendations for hepatitis A travel vaccinations. Based on new data on vaccine effectiveness postexposure, the recommendation is that the first dose of vaccine at any time before travel should protect most healthy persons. Another recommendation is to add immune globulin for high-risk groups who are traveling in less than two weeks to areas of high transmission and to use IG for persons less than 12 months old or who cannot receive vaccine.
Dr. Novak summarized the conclusions from the February ACIP meeting when these data were first introduced, as well as the activities of the hepatitis work group. In February, Dr. John Victor presented the results of a clinical trial comparing efficacy of hepatitis A vaccine and immune globulin after exposure. This was followed by a discussion of these data and the policy implications of using hepatitis A vaccine alone postexposure. The work group reviewed the available data with respect to vaccine age groups and patients with chronic liver disease and other underlying medical conditions. It considered patient characteristics associated with more severe outcomes, response to vaccine, and the risk of transmission in common scenarios where postexposure prophylaxis is given in the U.S., and then drew on the experiences of those countries currently using hepatitis A vaccine post exposure.
Potential benefits of being able to use vaccine include long-term protection, ease of administration, acceptability, and availability. There is currently only one U.S. supplier of immune globulin, and the cost of IG has risen considerably over the last five to ten years, making it similar to that of hepatitis A vaccine. A single adult dose of IG is now about $20, and the pediatric vaccine dose under government contract is about $12. The adult dose is about $19. Another benefit of being able to use hepatitis A vaccine is that it brings U.S. practice in line with many other countries that recommend vaccine as postexposure prophylaxis.
In the randomized clinical non-inferiority hepatitis A vaccine postexposure trial conducted in Almaty, Kazakhstan, 4,524 households or day-care contacts aged 2 to 40 years were enrolled. Contacts had been exposed to index cases within two weeks after the index case symptom onset and had no history of hepatitis A or receipt of hepatitis A vaccine or IG within the last six months, chronic liver disease, or contraindications to vaccine or IG. There was a 1-to-1 randomization within households or day-care centers to receive vaccine or IG within two weeks after the index case symptom onset. The primary outcome was clinical hepatitis A among contacts that met the following three criteria: Positive for IgM anti-HAV, ALT level at least twice the upper limit of normal during an episode of illness with no other obvious cause, and symptoms consistent with viral hepatitis.
The results of that study indicated that the efficacy of hepatitis A vaccine was similar to that of IG, i.e., the noninferiority criterion was met. Because of the study design, the point estimate for vaccine efficacy required an assumption about IG efficacy. Assuming 90 percent IG efficacy, the point estimate of vaccine efficacy was 86 percent with a 95 percent confidence interval of the upper bound of the relative risk of 76 percent. If 85 percent IG efficacy was assumed, the point estimate of vaccine efficacy was 80 percent with the upper bound of 64 percent.
Despite showing statistical noninferiority, the proportion of outcomes among vaccine recipients was slightly higher than among IG recipients, however the difference was small. Putting this in context, the risk of hepatitis A among vaccine recipients was never more than 1.5 percent greater than among IG recipients. This study provided evidence consistent with many previous studies that IG might attenuate clinical illness when given after exposure.
Looking at clinical endpoints by age, most cases were among children, so that was where the most inference was made, however the estimates for adults were similar. For the primary endpoint, 26 cases of laboratory-confirmed hepatitis A occurred among vaccine recipients and 18 occurred among IG recipients, yielding a relative risk among vaccine versus IG of 1.32. The one-sided 95 percent confidence interval upper bound of relative risk was 2.3, which was well within the prespecified margin of 3.0.
When stratified by age, the risk of hepatitis A was slightly higher among adults than in children in both the IG and vaccine groups. The point estimate of the relative risk for adults was very similar to that among children, but because of the relatively small number of adult participants, this stratified analysis has low power, so the confidence interval is wide. Similar findings were found when considering all suspected hepatitis A cases.
After considering these results, the consensus of the work-group members was that there was sufficient evidence to support equivalency of vaccine and IG in both children and adults 40 years or younger. Because of the advantages of vaccine and equivalence to IG, the work group decided to state a preference for vaccine in this age group: “For healthy persons age greater than or equal to 12 months to 40 years, hepatitis A vaccine at the age appropriate dose is preferred to IG because of vaccine’s advantages, including long term protection and ease of administration.”
At the time the Almaty study began, hepatitis A vaccine was not yet licensed down to 12 months in the U.S., thus children aged 12 to 24 months were excluded from the study population. The work group decided to include 12- to 23-month-olds in the vaccine recommendations. There is no evidence to suggest persistence of maternal antibody past 12 months, and the immunogenicity of the vaccine at 12 months is similar to that of 24 months. Currently, vaccine is licensed for use from 12 months in every country with a hepatitis A vaccine immunization program. Finally, current ACIP recommendations include this age group for pre-exposure vaccine use.
Unfortunately, results of the current study and previous information cannot answer all questions about how hepatitis A performs postexposure. First there is the question of age. Eligibility was restricted to age 40 and under in the Kazakhstan study. Most of the cases and study participants were fairly young, which is not surprising, given the epidemiology of hepatitis A in a country like Kazakhstan. All adults over age 40 are immune to hepatitis A, as are many young adults. No additional data are available to support preference for vaccine in these risk groups.
Considering the clinical characteristics of reported hepatitis A cases by age in 2005 received through the National Notifiable Disease Surveillance System (NNDSS), the severity of hepatitis A disease increases with increasing age, as evidenced by the proportion of hospitalizations and deaths due to hepatitis A. Because of the absence of data about vaccine performance in persons older than 40 years and the risk of hepatitis A increasing with age, the work group made the following recommendation: “For persons greater than 40 years, IG is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of hepatitis A in this age group. Vaccine can be used if IG cannot be obtained.”
The next population addressed was persons who were diagnosed with chronic disease, immunocompromised, and people with other medical conditions. The Almaty study excluded patients who reported a diagnosis of chronic liver disease based on the concern about the increased severity of hepatitis A. It did not explicitly exclude people with other medical conditions, but in general the study population was young and healthy. Patients with chronic liver disease or other chronic medical conditions are known to have poorer response to vaccine pre-exposure. In addition, patients with chronic liver disease have a higher risk of more severe disease outcomes.
Dr. Novak then presented available data with respect to immune response to a single hepatitis A dose in selected populations. Among HIV-infected patients, the three relevant studies report a wide range of seroconversion after one dose of hepatitis A: from 10 percent to 78 percent. Hepatitis A vaccination is recommended for patients with chronic liver disease, so there has been a fair amount of interest in studying the immunogenicity of the vaccine in these patients. In the three published studies of immunogenicity in these patients, the percent positive at four weeks ranges from 63 to 93 percent. It appears that the response rate is lowest in patients with decompensated cirrhosis. Finally, a few studies in liver and kidney transplant patients showed a much lower percent positive at four weeks.
A number of studies have indicated that the risk of severe outcomes from hepatitis A is higher among people with chronic liver disease (CLD). In a recent analysis of national death certificate data from 1999 to 2004 among 511 hepatitis A deaths, 229, or 45 percent, of deaths included a CLD-related ICD-10 code. The median age was 55 among CLD-related deaths and 69 among non-CLD-related deaths. Because of the suggestion of a suboptimal response to hepatitis A vaccine and the increased risk of severe hepatitis A outcomes in CLD patients, the work group decided to leave the current recommendation for IG in these groups: “IG should be used for children age less than 12 months, immunocompromised persons, persons who have been diagnosed with chronic liver disease, and persons for whom vaccine is contraindicated.”
The work group also reviewed the risk of transmission of hepatitis A virus and the common scenarios in which postexposure prophylaxis is given in the U.S. The most common setting for IG use as a postexposure prophylaxis currently is among household and other close personal contacts. Outbreaks in childcare centers used to require IG, but now these outbreaks are rare. In these settings, secondary attack rates of 15 to 30 percent are common, with higher rates of transmission occurring from infected young children than from adolescents and adults. This is probably the setting in which the risk of transmission is highest.
Another common scenario is after exposure to an infected food handler. Based on surveillance data, 3 to 7 percent of reported hepatitis A cases are food handlers. About 5 percent of food handlers worked while they were infectious and were felt to pose a transmission risk, i.e., people who might have been exposed to this food handler should be notified. However, the majority of food handlers do not transmit to patrons, as attack rates are generally low. In the context of these public notifications, an average of 350 IG doses per episode were administered. But there is a very broad range, and thousands of people received IG. The ability to use a vaccine might be quite beneficial in these circumstances.
Thus the working group recommended the following language: "Decisions to use vaccine or IG should take into account patient characteristics associated with more severe manifestations of hepatitis A. Additionally, the magnitude of the risk of hepatitis A virus transmission from the exposure should be considered."
At the last meeting the committee heard about postexposure policies of Canada, the UK, and other European countries. The work group looked for new data, and reconsidered available data with respect to the experience in Canada and the UK. In Canada, vaccine without IG is the preferred method of postexposure prophylaxis, while IG continues to be used for infants and the immunocompromised. The work group reviewed one report of possible breakthrough infections, but it was found to be a transmission chain involving outbreaks in several child day-care settings. It also tried to get additional information about the rationale of the U.K. recommendations, which limit vaccine to exposures within the previous seven days and IG for exposures greater than seven days or involving people older than 50 years with cirrhosis or chronic HBV or HCV infections. But the data available to inform these recommendations were very limited.
In summary, vaccine offers a number of advantages over IG, and the flexibility to use vaccine in some circumstances would be beneficial. Available data suggest that vaccine is efficacious postexposure, but not all populations were studied. Pre-exposure immunogenicity data suggest that there are suboptimal responses to vaccine in persons with chronic liver disease and other chronic medical conditions. Any recommendation the committee might make about the ability to use vaccine would be an off-label use, as it is not approved through FDA for this indication. Additional data are not likely to be forthcoming, and additional studies would be logistically difficult. So the committee needs to balance the practical public health implementation considerations against the limitations of the available information.
Among the materials provided to the committee was a copy of the current postexposure prophylaxis ACIP statement to provide background, as well as the new recommendations for postexposure prophylaxis. This document is meant to be a stand-alone MMWR ‘notice to readers’ with links to and from the current ACIP hepatitis A statement, thus it contains an introduction to the recommendation language to provide background information to the reader as to what changes were made and their rationale. These recommendations were clarified by appending the language from the current statement concerning common settings in which postexposure prophylaxis is given in the U.S. The only language change is the substitution of “IG or hepatitis A vaccine” for “IG.” In addition, the committee was provided with new travel recommendations for timing of pre-exposure vaccine dose.
The draft language for postexposure prophylaxis with hepatitis A vaccine is as follows: "Persons who recently have been exposed to hepatitis A virus and who previously have not received hepatitis A vaccine should be administered a single dose of vaccine or IG as soon as possible. Information about the relative efficacy of vaccine compared to IG postexposure is limited, and no data are available in persons aged greater than 40 years or those with underlying medical conditions.
"Therefore, decisions to use vaccine or IG should take into account patient characteristics associated with more severe manifestations of hepatitis A, including older age and chronic liver disease. Additionally, the magnitude of the risk of hepatitis A virus transmission from the exposure should be considered."
The next paragraphs deal with specific groups. "For healthy persons age greater than or equal to 12 months to 40 years, hepatitis A vaccine at the age appropriate dose is preferred to IG because of the vaccine's advantages, including long-term protection and ease of administration.
"For persons greater than 40 years, IG is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of hepatitis A in this age group. Vaccine can be used if IG cannot be obtained.
"IG should be used for children age less than 12 months, immunocompromised persons, persons who have been diagnosed with chronic liver disease, and persons for whom vaccine is contraindicated.
"Persons administered IG for whom hepatitis A vaccine is also recommended should receive a dose of vaccine simultaneously with IG. For persons who receive vaccine, the second dose should be administered according to the licensed schedule to complete the series. The efficacy of IG or vaccine when administered greater than two weeks after exposure has not been established."
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