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In favor: Allos, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morita, Womeodu, Abramson.
Abstained: Treanor (conflict).
The vote passed.
UNIVERSAL INFLUENZA VACCINATION
Presenters: Dr. Walter Orenstein, Emory University School of Public Health and Dr. Ben Schwartz, N.V.P.O.
Overview: Influenza vaccination strategies, information gaps, challenges to implementation of universal vaccination, Canadian data.
Emory University, C.D.C. and the N.V.P.O. called a meeting of government, professional medical societies, academia, school health, and industry to discuss the possibility of universal influenza vaccination. Although influenza vaccination coverage has improved, its mortality, hospitalizations and morbidity continue to be a burden. The present strategy is focused on persons at high risk of complications from influenza, particularly those ≥65 years, but this meeting discussed others aged 2 to 49 years. This group is not currently recommended for universal immunization, but 4 percent to 44 percent already are vaccinated, being household contacts and others of high-risk individuals.
Presentations were provided on the disease burden and program impact, information gaps and possible studies, and proposed potential strategies to phase in universal vaccination. Consideration of expanded influenza vaccination is being driven by the continued disease burden, particularly among the elderly and those at high risk; by low coverage among some of the recommended populations; and by the need to increase disease prevention and cost savings, strengthen the public health infrastructure, and improve pandemic preparedness.
The information gaps identified in the science of influenza and its prevention were:
Despite these gaps, several findings are well supported: the validity of a “U” shaped curve for hospitalization and mortality, significant illness burden throughout the population, higher rates in children than adults, a substantial role of children in transmission, reasonable V.E. in children and healthy adults, and better than reasonable V.E. among the elderly.
The challenges to implementation of universal influenza vaccination include a greater burden on the public health infrastructure and resources, since more doses of influenza vaccine would be delivered than all other vaccines combined. Universal vaccination may impose unintended opportunity costs to both current and new vaccines. The site of vaccine delivery was discussed, since this expansion would place a considerable burden on medical homes. Vaccinating in schools has its own set of challenges, as do other possible settings, and the role of public health in vaccine delivery is unclear.
Even without universal vaccination, there have been supply interruptions in the past, and the supply and demand issues are not likely to disappear in the time needed for manufacturers to build their production capacity. The public sector’s purchasing (or assured purchase) role continues to be debated. Public and health care sector acceptance will be essential to success, as will be settling the questions of financing. Ethical issues to ensure equitable distribution to all sectors of the population will require attention.
The experience was shared of Ontario’s universal influenza vaccination program, instituted in 2000. The program has increased vaccine coverage in all age groups surveyed (although there are no data on those aged less than 12 years) and lowered respiratory disease hospitalizations in all age groups. A media campaign facilitated its general acceptance. Further evaluations are being done. Still to be determined are the program’s impact on disease in children, its indirect effects, the potential of a coverage plateau, and the need for funding support and new delivery strategies. This program was implemented as part of their standard coverage without new funding.
In general, the expansion to universal vaccination was favored by all involved. Many of the latter at this meeting favored a stepwise approach to implementation, which could be more realistically consistent with vaccine supply. The approach would begin with universal vaccination of children, where there may be greater direct and indirect effects.
Several factors were acknowledged in the discussion of potential implementation strategies:
Presenter: Dr. Julie Morita, Harmonized Schedule Working Group Chair
Overview: Time line of the Working Group meetings, its members and consultants; proposed new harmonized schedule
Since its formation in February 2005, the Working Group has held monthly conference calls. The members revised the graphic and footnote portions of the harmonized schedule based on recommendations made over the last year. Revisions were reviewed by the C.D.C. leads of the hepatitis, pertussis, meningococcal and influenza Working Groups.
The committee was provided with two different versions of the schedule, addressing first the second draft of the universal hepatitis recommendations. A few edits to the hepatitis A footnote provided at this meeting would be incorporated later as well.
General format changes to the childhood schedule included:
Changes made to the childhood/adolescent schedule, by vaccine, were:
The catch-up schedule was modified as follows:
Dr. Allos moved to accept the harmonized schedule, with edits to change the terminology from developmental to age-based, and retaining the purple bar. Dr. Gilsdorf seconded the motion.
In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morita, Treanor, Womeodu, Abramson
The vote passed.
Presenter: Dr. John Treanor, Chair, Rotavirus Working Group Report
Overview: Background of A.C.I.P. recommendations regarding rotavirus vaccines; C.D.C. economic analysis; draft recommendations; in preparation for likely February 2006 recommendation vote.
The A.C.I.P. recommended universal rotavirus vaccination to address the disease burden of rotavirus disease. Another A.C.I.P. vote to recommend a rotavirus vaccine may be taken in February 2006. The disease impact estimates have not changed since last the A.C.I.P. decision, except perhaps to correct a slight underestimation. The disease burden is still significant in terms of total cases and their impact on families, hospitalizations, and deaths.
Merck has developed a new vaccine that is perhaps safer, with lower rates of excretion in stool, absence of intussusception, and lower rates of side effects such as diarrhea, vomiting, and fever. Efficacy is high in the prevention of rotavirus gastroenteritis of all levels of severity and in the prevention of related hospitalizations and utilization of medical services. A draft of the Working Group’s findings will be sent to A.C.I.P. members as soon as possible for their comment. The proposed recommendation should be ready when the vaccine is licensed, probably in February.
Cost Effectiveness of Rotavirus Vaccine
Presenter: Dr. Marc-Alain Widdowson, N.C.I.D.
Overview: Cost Effectiveness analysis methodology, disease burden data, data sources used, analysis results.
The last cost effectiveness (C.E.) analysis of rotavirus vaccination was done in 1998. An update was needed to assess the anticipated new vaccine and its different biologics, to include current disease burden estimates, and the cost of the vaccination’s possible side effects. New techniques were also in hand with which to model data uncertainty.
Methodology. A fictitious cohort of 100,000 children was followed from birth to age five years. The number of likely rotavirus cases was calculated, as was the number of outcomes if the cohort was fully vaccinated at 2, 4, and 6 months. The medical and non-medical costs for each outcome were estimated, along with the cost of a vaccine program and that of potential adverse reactions. This produced a cost-effectiveness ratio (net savings minus net program costs divided by the number of outcomes saved) for any one outcome. The C.E. ratio was calculated from the perspective of the healthcare payer (including only medical cost savings) and the societal perspective (including medical and non-medical cost savings).
A probabilistic Monte Carlo distribution technique was used to calculate multiple variables of disease burden distribution, multiplied by cost, to produce values for the median, 5th and 95th percentiles. This is done hundreds of times until the final distribution is a stable result.
Disease burden. The model first assumed that 75 percent of the cohort has one episode of rotavirus diarrhea by age five years. From that total is subtracted the number who die or have nonfatal outcomes requiring health care (for example, hospitalization, E.D., outpatient, and physician visits). The residual number is the number of rotavirus disease episodes not requiring any medical care. Distributions were charted of rotavirus cases and rotavirus deaths in children from birth to 5 years.
Data sources and their use were charted.
Analysis results were presented and diagramed, assuming 100 percent compliance.
The charted data of a sensitivity analysis demonstrated the dominance, , of hospitalization and E.D. visits. From a baseline of days of work lost, 50 percent more and 50 percent fewer days lost were factored to assess the societal impact. The result increased and reduced the baseline best-case estimate for the two different inputs by 32 dollars, which remained within the baseline estimate’s 5th and 95th percentiles.
The analysis’ conclusions were that, with 100 percent compliance with rotavirus vaccination, the rate of rotavirus-attributable diarrhea would drop an estimated 63 percent and related hospitalizations by 79 percent. There would likely be a net cost from the healthcare perspective whenever vaccination cost exceeds 67 dollars per vaccinee. From the societal perspective, a cost of vaccination exceeding 157 dollars per vaccinee will likely pose a net cost to society,.
Rotavirus Vaccination Related To Other Selected Childhood Immunizations
Presenter: Dr. Martin Meltzer, N.C.I.D.
Overview: C.E. of rotavirus vaccination compared to MMR, D.T.a.P., hepatitis B, varicella, pneumococcal conjugate and IPV vaccination.
In general, the newer vaccines are less cost saving than older vaccines. Because most averted rotavirus cases are uncomplicated, rotavirus vaccine's cost per Q.A.L.Y. averted is likely to exceed that of meningococcal vaccine (which is 138,000 dollars per Q.A.L.Y. averted). In terms of dollars per case averted, the cost of rotavirus vaccinations will be between that of pneumococcal and pertussis vaccinations.
One way to measure the values placed by society on an intervention is to calculate the time trade-off that is acceptable to avoid the disease’s effect on daily life, versus that to avoid a vaccine’s adverse effects. When the trade-offs to uncomplicated influenza cases and vaccine adverse events are compared, little time would be traded for the former while for the latter, long periods would be sacrificed. This indicates that those surveyed did not value greatly, in the units considered, avoiding an uncomplicated case of influenza, but greatly value avoiding vaccine-related side effects – even though the latter are very rare (and the low probability of such vaccine-related side effects was carefully explained to those surveyed). Including the value of time lost from work, a median of approximately 150 dollars per vaccination cost for rotavirus would not likely be cost saving. When the value of avoiding vaccine related side effects is added to the analyses, the use of the vaccine becomes even less cost effective. Data supporting the idea that the public greatly values avoiding vaccine-related side effects, however small the probabilities of such events, can be drawn from several vaccine experiences (for example, smallpox, swine flu, G.B.S., the move from D.T.w.P. to D.T.a.P., and from live to inactivated polio vaccine).
Anonymous peer review of this analysis was mostly positive, although some critical suggestions are now being examined. Those include clarification of methods, allowance for regional differences in rates (lost wages, reimbursements rather than true costs), and inclusion of the impact of herd effects.
Draft Recommendations for Pentavalent Bovine-Human Rotavirus (P.R.V.) Vaccine
Presenter: Dr. Umesh Parashar, N.C.I.D., for the A.C.I.P. Rotavirus Working Group
Overview: Background on rotavirus vaccine (P.R.V.) development, vaccine characteristics; draft recommendations: contraindications, precautions, special situations.
P.R.V., under the trade name Rotateq®, is an oral vaccine with a two-year shelf life when refrigerated. It contains five human bovine reassortants (a human P and four common human G serotypes) that are premixed with a buffer that resists gastric acid. It can be given orally to infants and the full series consists of 3 doses. The first of the three doses can be given at 6 to 12 weeks of age, and two subsequent doses at 1 to 2 month intervals after the preceding dose.
Rotavirus Efficacy and Safety (R.E.S.T. trial. The 2001 to 2005 P.R.V. clinical trial included slightly more than 70,000 infants aged 6 to 12 weeks. Results are summarized as follows:
Working Group discussions. Three options for recommendations were discussed: routine or universal use, a permissive recommendation, and a targeted high-risk recommendation. The Working Group suggested recommending routine immunization of infants with three doses at 2, 4, and 6 months of age, based on the large disease burden, particularly of hospitalizations, among U.S. children. One in 70 children will be hospitalized by age 5 years, constituting 5 percent of pediatric (to age 5) hospitalizations (total of 55,000 to 70,000 rotavirus hospitalizations each year).
Risk groups for severe rotavirus disease include low-birth weight or premature infants and certain maternal social characteristics (youth, smoking, unmarried). However, limiting vaccination to these risk groups would exclude a large number of infants who develop severe rotavirus disease requiring hospitalization, so a targeted vaccination strategy is not a practical option.
Draft Recommendations. Dose 1 should be limited to the age given during the R.E.S.T. trial (6 to 12 weeks of age) since vaccine safety was not evaluated for Dose 1 among those aged greater than 12 weeks, whose background rates of intussusception and natural disease are higher. The second and third doses should be given within the first year of life, with a four-week minimum interval between doses, as in the R.E.S.T. trial.
To resolve the quandary that the narrow dose 1 window might exclude the many children who are vaccinated at an older age, N.I.S. data were analyzed. The analysis showed that approximately 88 percent of infants aged 3 months received their first dose of D.T.P. vaccine and by age 12 months 96 percent of infants had received at least 1 dose of D.T.P. Thus, the 6 to 12 week age for dose one would miss only approximately 8 percent of infants who receive D.T.P.-1 later. This is still a large number of infants, but weighed against the limited data on safety of dose 1 in infants greater than 12 weeks, the Working Group thought it acceptable.
General recommendations: P.R.V. is recommended for both breast-fed and bottle-fed infants, as data show similar efficacy for both. Concomitant administration with other childhood vaccines is acceptable, and it can be given to infants with transient, mild illnesses.
Contraindications are altered immune competence (T- or B-cell deficiency), since this is a live (although attenuated) virus vaccine; and severe allergy to a vaccine component.
Precautions included moderate- to severe acute gastroenteritis or moderate- to severe febrile illness, pre-existing chronic gastrointestinal disease, and previous history of intussusception. For these, vaccination benefits and risks should be assessed on a case-by-case basis.
Special situations discussed include:
Next steps. F.D.A. licensure is expected early in 2006. The Working Group will refine the recommendations and circulate them for comment in the next 60 to 90 days. All the data will be reviewed at the February 2006 A.C.I.P. meeting.
MEASLES, MUMPS, RUBELLA and VARICELLA COMBINATION VACCINE
Presenter: Dr. Dalya Guris, N.I.P.
Overview: Composition of ProQuad®, the combination measles, mumps, rubella, and varicella vaccine; licensure basis; indications for use.
The ProQuad® combination measles, mumps, rubella and varicella (M.M.R.V.) vaccine has the same attenuated MMR virus composition and strength as MMR vaccine. It has a higher varicella zoster virus component than Varivax® (3.9910 versus 3.1310 PFUs). F.D.A. licensure was based on the antigenic components’ equivalent immunogenicity rather than the clinical efficacy.
An M.M.W.R. Notice to Reader will be issued to summarize the licensure data, the recommended routine schedules for M.M.R.V.; and M.M.R.V.’s indications, vaccination intervals, simultaneous administration, storage and handling. The current MMR and varicella recommendations are two routine doses of MMR vaccine and one of varicella vaccine, and a second dose of varicella vaccine in outbreak settings. M.M.R.V. is indicated for simultaneous vaccination against measles, mumps, rubella and varicella among children aged 12 months through 12 years. A.C.I.P. heard Merck’s data on ProQuad’s® immunogenicity, safety and concomitant administration in October 2004.
In 1999, A.C.I.P. stated a preference for licensed combination vaccines by the use of licensed and antigenically equivalent combination vaccines. M.M.R.V. can be administered for the first dose of MMR and varicella vaccines, and can also be used for MMR dose two and, in an outbreak, for the second varicella dose. It may be used whenever any components of the combination vaccine are indicated and the other components are not contraindicated, in the absence of products containing only the needed antigens or when administration of antigens would result in extra injections, and when the potential benefits of vaccination to the child outweigh the risk of adverse events associated with the extra antigen(s).
In the M.M.R.V. clinical trials, ProQuad® was administered to 4497 children aged 12 to 23 months and compared to MMR vaccine and varicella vaccine (Varivax®) given separately and concurrently. The children were monitored to day 42 post-vaccination.
M.M.R.V. had a higher rate of reactions than that of the concurrent administration group, in fever (approximately 50 percent higher, posing a greater risk of febrile seizures), measles-like rash (0.9 percent) and injection-site reactions (2.3 percent versus 1.5 percent). Data from V.A.E.R.S., V.S.D., and Merck are being assessed in an ongoing manner in post-licensure monitoring of serious adverse events (that is, hospitalization, prolonged hospital stay, death or life-threatening illness, permanent disability), as well as other medically important conditions (OMIC) such as febrile seizures.
V.A.E.R.S. post-marketing surveillance will include daily alerts of new or follow-up data (age at vaccination; onset interval in days; vaccination site, gender, symptoms, pre-existing conditions). These are immediately reviewed by C.D.C. and F.D.A. Higher priority will be given to serious and OMIC reports. V.A.E.R.S. nurses will obtain hospital discharge data and other relevant lab data. Additional monitoring tools will be used to compare the safety profiles of M.M.R.V. with MMR vaccine and varicella vaccine, stratified by age at vaccination, onset interval, reporting period, serious and non-serious reports. An example was shared of how this was done for Menactra® versus Menomune®, which provided the first G.B.S. signal. Code-reporting rates are also monitored to calculate an advance signal detection, by comparing one vaccine with all others in the same age group. Any unexpected outcome increase prompts a V.S.D. rapid cycle analysis of HMO data, using maximized sequential probability ratio testing and SCAN statistics to look for time clustering.
The Vaccine Safety Datalink (V.S.D.) is planning to monitor selected adverse event reports applying the rapid cycle analysis. The aim will be to identify any association of M.M.R.V. vaccine with adverse events among children vaccinated between ages 1 to 2 years and 4 to 6 years, compared to those vaccinated separately at the same visit in the five years before M.M.R.V. introduction. The rates of serious events 42 days post-vaccination will be compared with the age and season-adjusted expected rate of the baseline time period. The V.S.D. cohort includes approximately 90,000 children. An example was shared of the rapid cycle analysis done to examine rotavirus vaccine and intussusception, when the system successfully detected a rate increase at about week three post-vaccination.
The M.M.R.V. adverse events to be monitored are febrile seizure, thrombocytopenia, ataxia, encephalitis, arthritis, rash, rash and fever in 7 to 14 days of vaccination, and allergic reactions, including anaphylaxis, hives, and angioedema. Any other outcomes appearing at a higher rate will also be referred to the V.S.D. rapid cycle for further analysis.
Presenter: Dr. Greg Wallace, N.I.P.
Overview: Changes to the V.F.C. varicella resolution to authorize the purchase and use of M.M.R.V. in the V.F.C. program.
Dr. Wallace summarized the suggested changes to consolidate the A.C.I.P.’s MMR and varicella V.F.C. resolutions, to incorporate the new M.M.R.V. vaccine and the two-dose varicella recommendation in outbreak settings. The changes were as follow:
Dr. Campbell moved to approve the V.F.C. resolution and Dr. Gilsdorf seconded the motion.
|Jane D. Siegel, md; Emily Rhinehart, rn mph cic; Marguerite Jackson, PhD; Linda Chiarello, rn ms; the Healthcare Infection Control Practices Advisory Committee||Ranch hand advisory committee|
|Veterinary medicine advisory committee||Medical Devices Advisory Committee|
|External Advisory Committee on Cities and Communities||Wildlife Diversity Policy Advisory Committee|
|National Vaccine Advisory Committee (nvac)||Peer reviewed by the Arizona Department of Commerce Economic Research Advisory Committee|
|Food and drug administration national institutes of health advisory Committee on: transmissible spongiform||Advisory Committee, Cuyahoga Valley School-to-Career Consortium, Broadview Heights, Ohio 1996-2002|