Advisory committee on immunization practices




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Vote

In favor: Allos, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morita, Womeodu, Abramson.

Opposed: None

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:

  • Whether current influenza vaccine antigen content is optimal for elderly populations and if it should differ according to population (for example, L.A.I.V.C. or T.I.V. vaccine type).

  • Influenza disease burden and program impacts.

  • Indirect effects of vaccination.

  • Safety/effectiveness of repeated annual vaccination.

  • Cost- and prevention effectiveness.


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:

  • Improved coverage among the elderly and those at high risk must continue.

  • Monitoring of the implementation and its impacts must continue, with improved surveillance and diagnosis/diagnostic testing.

  • A reassessment of the disease burden and the cost effectiveness of expanded vaccination in adults (after the initial pediatric focus) should be done.


Discussion:

  • Dr. Cochi’s commented that the consolidation and extension of discussions of the last few years is a clear signal to A.C.I.P. and the Influenza Working Group of a consensus to begin moving forward in a phased manner to expand influenza vaccination in the U.S. Vaccine supply remains a “third rail,” but indications are that greater than 100 million doses will be produced next year. The Influenza Working Group will continue to discuss these matters.


HARMONIZED SCHEDULE

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:

  • Format: Adolescent ages were redefined to include the 15 year-old quadrivalent meningococcal vaccine recommendation. The age groups were previously delineated as 11 to 12, 13 to 18.

  • Yellow bars that denoted a single point in time were removed, because they were intended to represent a range of recommended ages when they should be administered.

  • Doses of vaccines hepatitis B and Hib vaccines that were permissible but not required (depending on the vaccine used), were italicized.


Changes made to the childhood/adolescent schedule, by vaccine, were:

  • The graphic and footnote for hepatitis B were altered to recommend strongly the birth dose, rather than extending from birth to age 1-2 months. There is stronger language for administering the birth dose, based on the mother's maternal hepatitis B surface antigen status.

  • The graphic and footnotes for tetanus and diphtheria toxoids and acellular pertussis vaccine (Tdap) were modified to replace tetanus and diphtheria toxoids (Td) for routine vaccination at age 11 to 12 years and catch-up at age 13 to 18 years.

  • The graphic and footnote for meningococcal vaccine were modified to recommend routine vaccination with M.C.V.4 at age 11 to 12 years and at age 15 for those still unvaccinated. The use of M.P.S.V.4 and M.C.V.4 among special populations was included, and marked with a pink broken line that is now used to denote vaccinations routinely recommended for selected populations.

  • The influenza vaccine footnote was updated to include the new risk groups of persons with conditions that can compromise respiratory function, and persons handling respiratory secretions. The M.M.W.R. reference was updated .

  • Hepatitis A’s bar for a new universal routine recommendation extends from age 12 to 23 months with no routine catch-up recommendation.


The catch-up schedule was modified as follows:

  • The footnote for hepatitis B catch-up for children aged 7 to 19 years was simplified to advise administering the three-dose series to all unvaccinated children and adolescents aged less than 19 years.

  • The Td recommendations were simplified to define the minimum interval for a vaccination, depending on the age of the first dose and the current age of the person being vaccinated. This allows for catch-up, including Tdap as one dose when an unvaccinated child is vaccinated.


Discussion:

  • The special population indication for M.C.V.4 did not extend back to age 11 because all children should be receiving it. However, those aged 12 to 14 years are not covered by the routine recommendation, nor are those aged 16 to 18 years. To show that, a dotted line indicated that only selected populations in those groups would receive M.C.V.4.

  • Dr. Middleman discussed the delineation of 11 to 12 year-olds as “pre-adolescent” and, essentially, treating them differently than the rest of the population. There is no similar variation for the 4 to 6 year-old group’s pre-K visit. She suggested that the schedule be updated to parallel the advances in the field of adolescent medicine. The standard terminology is “early adolescent,” but not every child enters the stages of adolescence at the same age. She strongly recommended eliminating the developmental terminology for 11 to 12 year-olds, as was done for the other age groups, as well as the purple bar denoting them. Considerations offered by the committee included:

    • The 11 to 12 year-old visit should be highlighted to ensure attention to the necessity of that visit, the importance of which may not be recalled by parents as easily as those of early childhood. However, Dr. Middleman hoped that pediatricians and physicians would consider catch-up at all ages.

    • The schedule is admittedly complex, and will be field tested.

    • Dr. Wallace stated that the purple bar is a visual method of emphasizing the recommended routine visit at age 11 to 12 years. N.I.P. is also considering a field test of separate adolescent and childhood schedules, in view of the growing adolescent schedule.

    • Dr. Baker reported the A.A.P.’s decision to use the descriptor “young adolescent” for this age group, rather than “preadolescent.”

  • It was clarified that the hepatitis A and B bars differed to comply with the previous day’s vote to allow, without a specific catch-up recommendation, immunization of unvaccinated children aged 12 to 23 months with hepatitis A vaccine before preschool or school entry.

  • Dr. Helms expressed concern that people with color blindness may not be able to see the entire schedule.

  • Dr. Friedland, of G.S.K., advised attention during the schedule’s field test to the readers’ comprehension of the time period of the bars. For example, he cited the D.T.a.P. bar’s ending at 24 months, but it should be given at 15 to 18 months. Dr. Morita responded that this is a problem with other vaccines as well (for example, influenza’s recommendation is from 6 to 23 months). Since one schedule cannot give that level of detail and remain readable, complete detail is provided in the footnotes.

  • Dr. Whitley-Williams noted the recommendation to vaccinate adolescents at high school entry. She suggested a focus on “unvaccinated adolescents” instead, since not all adolescents may be in high school and in view of states’ varying vaccination mandates. Dr. Abramson agreed; this was another reason to move from descriptive terminology and toward the use of age groups as descriptors.


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.


Discussion:

  • Dr. Wallace reminded the committee that the schedule should not be used to change recommendations; that should be done independently.

  • Dr. Lieu favored conforming the schedule to the A.A.P.’s language.

  • Dr. Naus thought that finalizing the schedule before field testing would be premature. However, Dr. Pickering noted the necessity of a rapid turnaround, since the harmonized schedule must be approved by the A.A.P. and A.A.F.P. as well.

  • Dr. Cochi saw the purple bar’s intent as to highlight the increasing importance of this visit for immunization as part of the adolescent visit, and to point out somehow that this is not a usual visit. Several members agreed that emphasis was needed, particularly since this period of time also will be the entrée for pending new vaccines. Dr. Tan stated the A.M.A.’s support of a specific delineation for the 11 to 12 year-old visit on the schedule.

  • Dr. Middleman agreed that the purple bar highlighted a visit that has been recommended for several years by the A.A.P. and A.A.F.P. She requested clarification that this approach be used for all ages, to guide providers during healthcare visits that are not solely for immunization.

  • Dr. Barbara Kuter, of Merck, suggested further harmonization of the MMR and varicella lines, to accommodate the new M.M.R.V. vaccine.

  • Ms. Murphy supported the use of the purple bar to highlight the visit at age 11 to 12 years, particularly since the vaccinator is generally the nurse or other staff, not the physician.

  • Dr. Middleman agreed to the schedule with the age definition replacing a developmental terminology.


Vote

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morita, Treanor, Womeodu, Abramson

Opposed: None

Abstained: None


The vote passed.


ROTAVIRUS


Background

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.

  • To estimate the number of episodes that would require healthcare, N.C.H.S. data from 1992 to 2002 were used to calculate the cumulative probability of a healthcare visit for diarrhea attributable to rotavirus, from birth to age five years.

  • The MarketScan database provided four years of employer medical cost data representing approximately 5 million enrollees. That was discounted by 3 percent for the societal and healthcare perspectives. A chart of the disease model input illustrated the estimated number of cases equivalent in the U.S. birth cohort.

  • Bureau of Labor Statistics data were used to chart the median, mean, and range of non-medical cost data.

  • Vaccine efficacy inputs were based on data from Merck’s (public domain) clinical trial.

  • The program costs used were illustrative only. The hypothetical vaccine price was derived from the cost of the three required doses of oral rotavirus vaccine, plus an assumed 10 dollars per dose administration factor, and an assumed cost for adverse reactions. The latter assumed a small risk of intussusception (or something similar), estimated at 1 per 50,000 vaccinees. The overall impact on the model of intussusception was approximately 25 cents.


Analysis results were presented and diagramed, assuming 100 percent compliance.

  • Health care perspective. Vaccination resulted in an estimated 63 percent reduction of all rotavirus diarrhea cases. It was also estimated that hospitalizations would decrease by 79 percent. The C.E. ratio per case averted from the healthcare perspective was charted against total cost per vaccinee, with the breakeven threshold (when cost just equals benefits) at 67 dollars total cost per vaccinee (range of 37 dollars to 149 dollars). Above 67 dollars total cost per vaccinee, the vaccine is likely to have a net cost from the healthcare perspective.

  • Societal perspective. The significant impact of days lost from work was clear in the charted results. The breakeven threshold was 167 dollars per vaccinee (three doses and administration costs), with a range of 110 dollars (or 41 dollars for children) to 241 dollars. Net costs are increasingly likely above 157 dollars total cost per vaccinee. When considering the outcome of costs per life year saved, the breakeven threshold values were similar to those calculated when considering cost-per-case averted as the outcome. However, whenever the thresholds were exceeded, the net cost per life year saved was approximately 1,000 times greater than the net cost per case averted.


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.


Discussion:

  • General appreciation of this analysis was expressed by the committee.

  • Dr. Treanor related the Working Group’s thinking that, beyond the important economic factors, a vaccine recommendation is based on the ability to reduce case totals. He found it hard to believe that parents would not value prevention of a case. If that were so, they would not even take the child to the doctor.

  • The assumption that only 75 percent of children will have at least one case of rotavirus by age five was thought to be conservative. Dr. Widdowson clarified that that the proportion of children having at least one episode of rotavirus diarrhea by the age of 5 years ranges from 65 percent to 95 percent, but even at those ranges, the model’s results changed little.

  • Dr. Offit agreed that the difficulty in finding a child aged less than 5 years who is seronegative suggests that the assumption of 2.7 million cases of rotavirus per year is an underestimate. Current studies by David Matson are likely to demonstrate that. He also questioned estimating the vaccine’s cost between that for pneumococcus and pertussis, when it has not yet been priced.

  • Dr. Plotkin asked why the model’s 79 percent hospitalization reduction was so much lower than the most valid figure to date, from the R.E.S.T. study, of 97 percent. Dr. Widdowson explained that the R.E.S.T. figure was for vaccine efficacy, which would not include children aged less than 6 months who are unvaccinated. Including them dropped the V.E. Dr. Plotkin objected that this risked an incorrect inference of lower vaccine efficacy. He also noted that the numbers of the analysis indicate rotavirus vaccine to be a reasonable investment, and he questioned the analysis’ value in any decision about using the vaccine.

  • Dr. Laura York, of Wyeth Pharmaceuticals, noted that the characterization of the cost of pneumococcal vaccination stemmed from older economic studies, which would likely have a different conclusion today. She urged inclusion to this analysis of the herd immunity effect and a more holistic view of vaccines’ beneficial impact on communities as a whole.

  • Dr. Lieu appreciated the thoughtful and methodologically well-constructed analysis. However, she expected the current information to be inadequate for an A.C.I.P. decision. The unknown vaccine price defeats any realistic C.E. determination, and the cost per case (termed by Dr. Meltzer as between pneumococcus and pertussis, ) will not be clear to many but clinicians who know those illnesses’ severity, so those relative values remain unclear. While economics are not the dominant factor in A.C.I.P. decisions, this analysis needs to go further to be more useful. The time trade-off, for example, includes a tremendous variation among people relative to prevented influenza. That is true for most minor illness, but when the illness’ complications are presented (for example, otitis media or pneumonia), they raise the time value traded. The study needs to be more systematic and refined to address rotavirus in particular.

  • Dr. Roger Glass, of C.D.C., pointed out that epidemiologic data indicate the asymptomatic character of infections in the first two months of life. Since those are not counted, there is no 100 percent disease incidence measured. He also noted that this vaccine requires three doses to be fully effective. That is not completed until 6 months of age, leaving the infant potentially vulnerable over three rotavirus seasons.

  • Dr. Penny Heaton, of Merck, clarified that their R.E.S.T. efficacy studies were of children vaccinated year-round, so they would be protected through the current and following season.


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:

  • Overall V.E. monitored among 7000 infants for all outcomes was 74 percent, and 98 percent for severe disease outcomes (for example, dehydration, hospitalization). Efficacy in reducing healthcare utilization was measured by hospitalizations and emergency department (E.D.) visits among all 70,000, and office visits in a subset. More than 90 percent of hospitalizations and E.D. visits were eliminated, as were approximately 85 percent of office visits.

  • Intussusception was monitored for 42 days following vaccination; six cases were identified in vaccinees and five cases in placebo recipients. Because the first few weeks after dose 1 was the critical window for intussusception clustering with Rotashield®, that period was closely studied. No cases of intussusception were observed in the R.E.S.T. trial among vaccine recipients after dose 1, and a few cases were observed following doses 2 and 3. The overall relative risk was calculated at 1.6; the confidence interval included 1.0 but was not statistically significant. The trial concluded that the vaccine was not associated with intussusception among the infants in this trial.


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:

  • Considerations for premature infants who are clinically unstable and at an increased risk of severe disease from rotavirus infection. There is no restriction for infants who had recent administration of any antibody-containing blood products.

  • Infants with immunocompromised household members. Exposing the latter to even an attenuated virus with low shedding rates is not desirable, but vaccinating the infant reduces their risk of being infected with and transmitting wild virus. The Working Group concluded that these infants can be vaccinated to protect the household member.

  • Infant regurgitation of vaccine dose during or shortly after administration: re-administration is not recommended. There are few data, but it is thought that even a partial dose will provide some immunity.


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.


Discussion:

  • Merck conducted surveys of provider end-users and C.D.C. is planning the same. An Immunization Safety Office (I.S.O.) contractor is surveying pediatricians, and family practitioners will be surveyed in the first quarter of 2006.

  • The Working Group considered a recommendation to immunize premature but stable infants in the nursery who are 6 chronological weeks of age. Dr. Baker urged that this be included and clearly stated to avoid any confusion.

  • Dr. Neuzil suggested that the Working Group carefully consider the risk benefit of the relative contraindications based on immunogenicity, since that may essentially prevent the child from ever beginning the vaccination series.

  • Dr. Baylor reported that post-licensure studies are in discussion. F.D.A. will require sub-studies as well.

  • Dr. Lieu requested greater clarity on the economic analysis of vaccine cost and C.E. for P.R.V., and for a comparison between the likely number of rotavirus hospitalizations and cases versus that of influenza (with a universal immunization recommendation pending) and other existing and prospective immunization programs.

  • A two-dose schedule of a monovalent, G-1 serotype (the most common attenuated) vaccine made by G.S.K. is used mostly in Latin America. Its V.E. is good against severe disease, very comparable to Merck’s. One question is about its efficacy with serotype G2, which is from a different genogroup than G strains 1, 3, 4, or 9. However, G2 is a less common serotype in most settings. That vaccine appears to be safe.

  • Dr. Penina Haber cited V.A.E.R.S.’ sensitivity to detect rare events, and reported their plans to use rapid-cycle analysis.

  • Dr. Penny Heaton, of Merck, reported that they will conduct the post-licensure study, which is in design with F.D.A. More information will be available in February. She also noted that R.E.S.T. required the premature infants to be healthy, so they have no data on giving the vaccine to neonates in the hospital.

  • Dr. Mark Feinberg, of Merck, stated that the vaccine price was not yet set, but will be provided before F.D.A. licensure and an A.C.I.P. recommendation request.

  • Dr. Jim Alexander, of N.I.P., reported the Working Group’s debate over age at vaccination. They discussed how the tight time limits could miss vaccination opportunities, which is a concern. Dr. Neuzil agreed. She would not make moderate fever a relative contraindication in a two-month-old, because the infant could potentially not return until after the time frame, resulting in no vaccination at all.

  • Dr. Heaton described the administration of the vaccine. It is stored refrigerated in a plastic tube with a twist-off cap which, when twisted, breaks the seal. The end of the cap is tapered for direct administration to the infant; a good method has been to give half in one cheek and half in the other. The vaccine is stable for 24 months, of which approximately 3 to 6 months is in the manufacturing and shipping process, leaving 18 months in the clinic.

  • Dr. Andrew McKnight, of G.S.K., confirmed that G.S.K. is discussing licensure requirements for Rotarix® with the F.D.A.


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.


V.F.C. Resolution

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:

  • M.M.R.V. can be used for the two recommended doses of MMR-containing vaccine among those aged 12 months to 12 years. It is not indicated for those aged less than 1 year, even during measles outbreaks.

  • Precautions: Tuberculosis was added for those who have not yet started active treatment. For the MMR component: cytomegalovirus immune globulin therapy was added to text on time intervals for certain immunoglobulins before MMR can be given.

  • M.M.R.V. vaccination eligibility is stated for those aged 12 months to 18 years without evidence of varicella immunity.

  • Dosage. A single routine dose is recommended, or two doses for catch-up of those age ≥13 years. In varicella outbreak settings, a second M.M.R.V. dose may be administered to children aged ≥12 months who need additional protection from varicella disease. M.M.R.V. should not be administered for the second dose of MMR except when a dose of varicella vaccine is also indicated or if no MMR is available at the time of the second dose. (This text was added to avoid missed opportunities and to include those who lack the first dose of varicella and who are indicated for both the first dose of varicella and the second dose of MMR.)

  • Intervals. The differing intervals for those older and younger than 13 years are detailed; reference to the package inserts for dosage information is advised.

  • Contraindications: The specific contraindications for AIDS and certain other immune deficiencies was removed; text on vaccine use by nursing mothers was added.


Discussion:

  • Dr. Lieu asked about the practical connotations of this vote; that is, the amount to be spent and the rationale for such an expenditure. Dr. Wallace responded that the grantees’ uptake would determine that, as well as the V.F.C. vaccine contract price, which cannot be negotiated before the V.F.C. resolution passes.

  • The second dose of varicella vaccine is likely to be discussed at the February or June A.C.I.P. meeting. The workgroup is evaluating that and other issues.

  • The time intervals since receipt of immune globulin for the MMR and varicella components was taken from those vaccines’ respective tables. That can be updated when the recommendations are updated.

  • The minimum interval difference was taken from the package insert; a three month minimum interval for those aged less than 13 years and requiring two doses. The time period is shorter for those aged ≥13 years. Dr. Kuter reported Merck’s need to fit the vaccine into the routine immunization schedule’s 3-month interval, but their studies looked at 4 to 8 weeks. The European label has a one-month interval for the product despite the lack of data. Dr. Marcuse raised the risk of confusion if the A.C.I.P. recommends differently than the package insert. In terms of immunogenicity, Dr. Abramson thought that separating two live viral vaccines by a month would provide reasonable immunogenicity. Dr. Pickering added that the three month interval was licensed based on active disease, but felt that six months would make little difference. Dr. Abramson asked the workgroup to look at that issue and recommend on it to the full committee.

  • Dr. Barbara Watson, of the Philadelphia health department, reported that of their 400 V.F.C. providers, only two are fully private, and they already have M.M.R.V. She hoped that the measles vaccine experience of coverage disparity, which led to 30 percent coverage and outbreaks, would not be repeated.


Dr. Campbell moved to approve the V.F.C. resolution and Dr. Gilsdorf seconded the motion.

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