Draft Conclusions of the Third Meeting of the SAGE Working Group on Measles January 29-30, 2009, Geneva

Transcription

1 Draft Conclusions of the Third Meeting of the SAGE Working Group on Measles January 29-30, 2009, Geneva Introduction The objectives of the 3 rd Meeting of the SAGE Working Group on Measles were 1) to review the evidence and formulate draft recommendations for when countries should introduce a second dose of measles vaccine delivered through routine services and 2) to review the programme of work to assess the feasibility and cost-effectiveness of global measles elimination. The reports from the first two meetings of the working group and subsequent SAGE recommendations dealing with the optimal age for administration of the first dose and the recommended interval between follow-up campaigns can be found in annexes 1-4. To facilitate communication of its findings, the working group formulated definitions for terminology that describes administration of measles-containing vaccine (MCV) doses. Regions may use these terms in different ways. However, for the purposes of this report, the following definitions apply: Definitions "First dose" and "second dose" refer to the doses of measles vaccine an individual receives and, thus, have clinical implications for the likelihood that a vaccinated individual is protected against measles. Receipt of 1 dose at 9 months of age is associated with an average vaccine effectiveness of 85%; receipt of a 2 nd dose administered at >12 months of age increases vaccine effectiveness to >95%. "MCV1" and "MCV2" refer to "measles containing vaccine dose 1" and "measles containing vaccine dose 2". These are programmatically scheduled vaccinations, which can be delivered through routine services, intensification of routine services, or mass vaccination campaigns. Regardless of the mode of delivery, where possible, the dose should be recorded on the child's immunization card. The "second opportunity for measles immunization" refers to catch-up and follow-up campaigns. These are supplementary immunization activities in which children are vaccinated regardless of prior history of measles vaccination or measles disease. The objective of the "second opportunity for measles immunization" is to protect children who missed their first dose or did not seroconvert following their first dose. In this document use of the term "MCV1" implies delivery through routine services. Because MCV2 can be delivered in routine or campaign mode, the term "routine MCV2" will be used to refer to the 2 nd dose of measles-containing vaccine that is delivered through routine services.

2 Draft recommendations The draft recommendations for introduction of routine MCV2 will be presented for decision at the April 2009 SAGE Meeting and are summarized under 3 headings below. The evidence and discussions supporting these recommendations are described in the proceedings of the meeting. 1. Criteria for starting routine MCV2 MCV2 may be added to the routine immunization schedule in countries that have achieved > 80% MCV1 coverage at the national level for three consecutive years as determined by WHO/UNICEF estimates. In general, countries that do not meet this criterion should prioritize improving MCV1 coverage and conducting high quality follow-up campaigns, rather than adding MCV2 to their routine schedule. Before introduction of routine MCV2, countries should determine a suitable age for administration of this dose, establish a system for recording doses both for the individual (e.g., an immunization card) and for the health system (e.g., a vaccination register), and conduct training of health staff to ensure timely scheduling of doses and tracking of defaulters. Because addition of routine MCV2 only covers a single birth cohort and will take time to achieve high coverage, countries should not stop regular follow-up campaigns. Accumulation of susceptible persons should continue to be monitored subsequent to routine MCV2 introduction and a follow-up campaign conducted whenever the number susceptible pre-school age children approaches the size of a birth cohort. Experience in the Americas has shown that measles elimination can be achieved with high MCV1 coverage and regular high quality SIAs. Hence, addition of routine MCV2 is not necessary for stopping measles transmission. Nevertheless, a country may decide to add MCV2 in their routine schedule (while continuing SIAs) for one or more of the following reasons: 1) to establish a well-child visit in the 2 nd year of life; 2) to slow the accumulation of susceptible children and thereby allow lengthening of the inter-campaign interval; and 3) to decrease reliance on SIAs and eventually stop SIAs once high population immunity (>95%) can be maintained with a routine two dose schedule alone. 2. Optimal timing of routine MCV2 Countries with ongoing measles transmission and MCV1 delivered at 9 months of age, should administer the routine MCV2 at months of age. The minimum interval between MCV1 and MCV2 is one month. Both MCV1 and MCV2 should be recorded on the child's immunization card and in the clinic vaccination register. Measles vaccination history should be screened at schoolentry and children, lacking evidence of receipt of two doses, should be vaccinated. In countries with very low measles transmission (i.e., near elimination) and hence a low risk of measles infection among infants, MCV1 can be administered at 12 months to take advantage of higher sero-conversion rates achieved at this age. In this setting, routine MCV2 can be delivered at any time between 13 months of age and school entry. The optimal age for administration of routine MCV2 is based on programmatic considerations that enable achieving the highest population immunity. Administration of MCV2 at months ensures early protection of the individual, slows accumulation of susceptible young children, and may correspond with other routine immunizations (e.g. a fourth DTP dose.) If MCV1 coverage is high (>90%) and school enrollment is high (>95%), administration of routine MCV2 at school entry may be an effective strategy to achieve high coverage and prevent outbreaks in schools. 2

3 3. Criteria for stopping follow-up campaigns Cessation of SIAs is a serious decision and should be considered only when greater than 90-95% immunization coverage has been achieved at the national level for both MCV1 and routine MCV2 as determined by the most accurate means available (e.g., a well conducted population-based survey, WHO/UNICEF estimates.) Before stopping follow-up SIAs, a careful review should be conducted by a national committee (e.g., the national immunization advisory group). The committee should review the following: historical immunization coverage data (for MCV1, routine MCV2, and SIAs) both at the national and district 1 level, the degree of heterogeneity of routine coverage among districts, the population immunity profile, the predicted rate of accumulation of susceptibles in the absence of SIAs, the epidemiology of measles, and the performance of the measles surveillance system. In the absence of adequate data or in the event that data suggests that cessation of SIAs would allow population immunity to drop below the herd immunity threshold (93-95%), follow-up SIAs should continue to be conducted. In settings where nationwide SIAs are not possible (e.g., due to civil unrest, political instability, or financial constraints), sub-national SIAs can be conducted to slow the accumulation of susceptibles The global recommendations proposed for SAGE regarding the introduction of a second routine dose and stopping SIAs do not conflict with current regional recommendations, though some regional recommendations require additional or more stringent criteria. 1 A district is defined as the third administrative level (nation is the first, province is the second.) 3

4 Meeting Proceedings The meeting was opened by Dr. Philippe Duclos, who emphasized that the most critical outcome of the meeting was draft recommendations that can be presented to SAGE at the April 2009 meeting. Although the available evidence may not be strong according to the GRADE approach, further analyses are unlikely to significantly clarify the issues at hand. The list of participants and agenda for the meeting are in annexes 5 and 6. Meeting objective #1: Criteria for introduction of routine MCV2 Report on the November 2008 SAGE and expected outcomes Key conclusions regarding measles at the November 2008 SAGE meeting included: Reaching all children with 2 doses of measles vaccine should be the standard for all national immunization programmes Delivery of the second dose can either be on a continuous basis (e.g., through routine services) or given periodically (e.g., through campaigns) depending on which method achieves the higher coverage Reaching every child with two doses of measles vaccine will require greater investment in systems to record and monitor administration of each dose Because achievement of population immunity of >93% 95% homogeneously in all geographical areas is required to prevent measles epidemics, reaching and maintaining very high immunization coverage remains the basis of effective measles control. The current regional criteria for starting routine MCV2 and stopping SIAs were reviewed: Current regional recommendations for introducing a second routine dose AFRO: A routine second dose should be introduced when coverage with the single routine dose reaches 80% for 3 consecutive years and 1 of 2 surveillance system performance indicators are met. EMRO: A routine second dose should be introduced when coverage with the single routine dose reaches 80% for 3 consecutive years. EURO: Two routine doses are administered in all countries PAHO: When introducing a second routine dose, it is necessary to establish the best age for vaccination, define a denominator for the targeted children, implement a nominal registry, monitor coverage, identify groups of unvaccinated children, and follow up vaccinated children. SEARO: Every child should receive two doses through either routine services or SIAs, depending on which approach is best able to achieve high coverage (>90%.) WPRO: A routine second dose should be introduced when coverage with the single routine dose reaches 80% for 3 consecutive years. Current regional recommendations for stopping SIAs AFRO: Continue SIAs until coverage with both routine doses reaches 90% at national level. EMRO: Continue SIAs until coverage with both routine doses reaches and is maintained at 90% at national and district levels. EURO: No regular SIAs conducted PAHO: Continue SIAs until coverage with both routine doses reaches and is maintained at 95% among all municipalities. SEARO: Continue SIAs until coverage with both routine doses reaches 90% WPRO: Criteria not stated 4

5 The key questions to be addressed by the working were laid out in the diagram below: Figure 1: Key questions for the third meeting of the SAGE WGM (yellow boxes) Increasing immunization system capacity Decreasing risk of measles outbreaks What is the best method to accelerate control? Single routine dose, No SIAs 1 country (India, SEARO) Single routine dose, Regular SIAs 60 countries AFRO 40/46 (all except those indicated below) AMRO 9/35 (Bolivia, Dominican Republic, Ecuador, Guatemala, Haiti, Honduras, Nicaragua, Peru, Venezuela) EMRO 4/21 (Djibouti, Pakistan, Somalia, Sudan) SEARO 3/11 (Bangladesh, Nepal, Timor Leste) WPRO 4/27 (Cambodia, Lao People's Dem. Rep., Solomon Is., Vanuatu) Two routine doses, Regular SIAs 54 countries AFRO 3/46 (Lesotho, South Africa, Swaziland) AMRO 24/35 (all except those otherwise indicated) EMRO 12/21 (all except those otherwise indicated) EURO 2/53 (Albania, Georgia) SEARO 2/11 (Indonesia, Myanmar) WPRO 11/27 (China, Cook Is., Fiji, Kiribati, Marshall Is., Mongolia, Nauru, Niue, Papua New Guinea, Philippines, Samoa) Two routine doses, One-time catch-up 37 countries AFRO 3/46 (Algeria, Mauritius, Seychelles) AMRO 1/35 (Canada) EMRO 4/21 (Bahrain, Libyan Arab Jamahiriya, Morocco, Oman) EURO 16/53 (Armenia, Azerbaijan, Cyprus, Ireland, Italy, Kazakhstan, Kyrgyzstan, Rep. of Moldova, Romania, Serbia, Slovakia, Tajikistan, Turkey, Turkmenistan, UK, Uzbekistan) SEARO 4/11 (Bhutan, Dem. People's Rep. of Korea, Maldives, Sri Lanka) WPRO 9/27 (Australia, Malaysia, Micronesia, New Zealand, Palau, Rep. of Korea, Samoa, Tonga, Tuvalu) Two routine doses, No SIAs 41 countries AMRO 1/35 (United States of America) EMRO 1/21 (Kuwait) EURO 35/53 (all except those otherwise indicated above) SEARO 1/11 (Thailand) WPRO 3/27 (Brunei Darussalam, Japan, Singapore) When is it beneficial to introduce a second routine dose? When is it safe to eliminate SIAs? 5

6 Field effectiveness of measles vaccine Preliminary results of a literature review on the field effectiveness of MCV at different ages were presented. The review was based on a Medline and PubMed search using a defined search strategy with explicit inclusion and exclusion criteria. Only English language articles with estimates of MCV field effectiveness obtained from case-control and cohort studies were included (n=66); studies using the screening method were excluded. Summary statistics were calculated for the published vaccine effectiveness point estimates by age of receipt of the MCV1 (9-11 months vs. 12+ months). Based on 43 point estimates, the median field effectiveness of one dose of measles vaccine administered at 9-11 months of age was 77% (inter-quartile range: 62%-91%) Using data from three studies, the vaccine effectiveness following two doses of measles vaccine (MCV1 given at 9-11 months and MCV2 given at >12 months) was 96% (inter-quartile range: 95%-99% ). Only one study compared the vaccine effectiveness of two doses versus one dose, whereby MCV1 was given at age 9-11 months the estimated 2-dose VE was 90%. Findings across studies cannot be directly compared because of different study settings, vaccine handling practices, study designs, and the real possibility of different degrees of misclassification of both case and vaccination status across studies. Nevertheless, the findings are consistent with results from immunogenicity studies and suggest two doses of measles vaccine protect a higher proportion of children than one dose alone, especially if the first dose is administered at 9-11 months of age. Figure 2: Vaccine effectiveness point estimates when first dose given at 9-11 months, by groups compared in study (1 dose only, 2 doses vs. 0, and 2 doses vs. 1) 6

7 Preliminary findings from the literature review of the field effectiveness of MCV are consistent with immunogenicity studies and suggest two doses of measles vaccine protect a higher proportion of children than one dose alone, especially if the first dose is administered at 9-11 months of age. Country experience: Measles elimination in the Americas An analysis of whether addition of a second routine dose shortened the time to measles elimination for countries in Latin America was presented. In this region almost all countries have high routine first dose coverage and were conducting high coverage SIAs. Propensity scores based on vaccination coverage, population characteristics, and surveillance quality were used to match 15 (out of 21) countries so that similar demographic and programmatic characteristics were represented in both the single routine dose and two routine dose groups. Figure 3: Propensity-score matched survival analysis of time to elimination in 15 PAHO countries The conclusion from this analysis was that in Latin America,where countries have high routine and campaign coverage, use of a second routine dose did not affect time to measles elimination when administered at school entry. This analysis supports findings from modelling that high first dose coverage and high quality SIAs are sufficient to achieve elimination. The results also indicated that successful implementation of immunization activities was more important to achieving elimination than the underlying socio-demographic circumstances of the country. These findings are limited by the ecological nature of the analysis and may not be applicable to settings in which MCV2 is administered at an earlier age (e.g., in the 2 nd year of life) or settings were SIAs are not being conducted or only achieve low coverage. In PAHO, where countries have high routine and campaign coverage, a second routine dose when administered at the age of entry to school did not affect time to measles elimination. 7

8 Country experience: An analysis of reported coverage and incidence data This approach used over 4,500 country-years of observation compiled from the WHO database of annual country-specific measles coverage data (MCV1, routine MCV2, and SIAs) and measles incidence. These data were analysed using a negative binomial regression model. The figure below shows the results as a plot of measles incidence rate (on vertical axis) against routine MCV2 coverage (on horizontal axis) under 10 scenarios. The top panel of 5 plots refer to years when no SIAs were done and the bottom panel of 5 plots are in the presence of SIAs. Each plot refers to a different range of MCV1 coverage from 0-39% on the extreme left to % on the extreme right. Within each plot, the slope of the line reflects the effect of increasing MCV2 coverage on measles incidence - the steeper the negative slope the greater the effect. As data were sparse for scenarios with MCV1 coverage <60%, these were not discussed in detail. There appeared to be a consistent negative slope in the regression lines in all plots which was more marked in the absence of SIAs and for MCV1 coverage in the range 60-79% and 80-89%. Preliminary results showed that for every 1% increase in MCV1 there was a 2% reduction in reported incidence and for every 1% increase in MCV2 coverage measles incidence decreased by 0.5%. The completion of a nationwide SIA, irrespective of SIA coverage, was associated with a 50% reduction in reported incidence in the subsequent year. However, the effects of SIAs are not directly comparable to the effects of routine doses because SIAs impact multiple birth cohorts simultaneously whereas routine doses only impact one birth cohort at a time. Figure 4: Measles incidence by MCV2 coverage grouped according to MCV1 coverage (0-39%, 40-59%, 60-79%, 80-89% and 90+%) and the presence (bottom panel) or absence of SIAs (top panel) This analysis, although preliminary, did provide evidence for a measurable impact of MCV2 coverage on reducing measles incidence across a range of MCV1 values both with and without SIAs. 8

9 Country practice: The optimal age to give routine MCV2 Current recommendations for the age of administration of MCV1 and MCV2 were presented as well as country practice and key programmatic considerations in determining optimal timing of these doses. The 2004 WHO position paper does not address variation among routine MCV1 and MCV2 schedules across countries or indicate that the timing of routine MCV2 is, in part, dependent on the age of administration of MCV1. Among the 132 countries that provide measles vaccine in a routine two dose schedule, the two most commonly used schedules are: 1) MCV1 at 9 months and MCV2 at months, or 2) MCV1 at 12 months and MCV2 at age of school-entry. The trade-offs between different ages of vaccination include: a) administration below 12 months reduces risk of measles among infants but is associated with lower sero-conversion rates; b) the need to vaccinate before the peak in exposure to measles; c) certain ages may be programmatically advantageous for achieving high coverage; and d) opportunities to link a second routine dose with other health interventions (e.g. de-worming, administration of vitamin A, or a 4 th dose of DTP). Giving routine MCV2 at the age of entry to school has been effective in AMRO, where routine and SIA coverage is high. Currently 61 out of 143 countries have indicated that they implement some type of school-based immunization program. However, where measles transmission is ongoing and school attendance is not high, a month schedule is preferable. While a second dose can be given as early as one month following the first dose, the WGM agreed that the age for a routine second dose should, in general, not be younger than 15 months to allow sufficient time for children to receive their first dose, considering that SAGE has already recommended that shifting MCV1 to 12 months is a rational and desirable choice as countries approach measles elimination. Additionally, a month routine MCV2 may coincide with the age of administration of a fourth DTP dose. Table 1: Routine MCV2 schedules Type of schedule Early & 2nd year Early & school-age 1st & 2nd year 1-2 years & school-age Current recommendation for age of administration of routine MCV2 (WHO Position Papers, WER April 2004 and WER January 2007) A second routine dose is generally administered at school age, but can be given as early as one month following the first dose, depending on the local programmatic and epidemiologic situation Ages of administration AFRO AMRO EMRO EURO SEARO WPRO 9 M & M a 20 9 M & 4-6 Y M & M b M & 3-7 Y years & older Proportion of countries with routine MCV2 a) China (8 months & months); Papua New Guinea (6 months & 9 months) b) Germany (1st dose months); Austria (1st dose months) c) Italy (2nd dose 5-12 years); Lithuania (2nd dose 6-12 years) M & >7 Y c Total 6/46 26/35 17/21 53/53 7/11 23/27 132/193 9

10 Of the 132 countries that provide measles vaccine in a routine two dose schedule, 80% (106) administer MCV at either 9 months and months, or 12 months and school-entry age. For countries with on-going transmission who meet the criteria for adding routine MCV2, this dose is recommended at months of age to reduce build up of susceptibles among preschool age children. For countries near or at elimination, risk of infection among infants is low and if MCV1 coverage at 12 months of age is high the build-up susceptibles is correspondingly slow. In such settings, delaying routine MCV2 until school-entry age poses little risk and may achieve very high coverage if a school-entry requirement is implemented. In the African region many countries using a 9-month MCV1 schedule are still experiencing cases among infants and, thus, should not increase the age of administration of MCV1. In addition, it was noted that high routine MCV2 coverage would be very difficult to achieve for African countries that have not yet achieved 80% MCV1 coverage. Results from modeling Three independently developed models were used to assess the projected effects and costs associated with different immunization strategies. These analyses were specifically designed to answer the following questions (see Figure 1): 1) What is the best method to accelerate measles control in settings with a one dose strategy (e.g., States in India)? Which of the following have the most impact and are cost-effective: increasing routine coverage, providing a second routine dose, or implementing SIAs? 2) In selected African countries and Cambodia, would a second routine dose have added benefit in the continued presence of SIAs and, if so, is an 18 month or 7 year age of administration more advantageous? 3) In selected Latin American countries where MCV1 coverage is high and MCV2 coverage is variable, are continued SIAs necessary to maintain elimination? All three models evaluated the same countries with many of the same parameters and data, including: projected population sizes, coverage and ages of administration for routine doses and SIAs, frequency of SIAs, CFRs, and vaccine efficacy. All models assumed homogenous mixing, homogenous vaccination coverage within each country, no delays in vaccination, and did not incorporate the costs of outbreak investigation or case treatment. Similar outputs were produced, including reduction in cases, mortality, and DALYs and the associated cost-effectiveness ratios. The results of each of these three models are presented below followed by the differences between the models. 10

11 Model 1: A fully dynamic model developed by Levin/Burgess Results of a fully dynamic model based on a series of differential equations that incorporate seasonality and use age-specific forces of infection that adjust according to the level of population immunity were presented. Key findings 1) What is the best method to accelerate disease control in India? o 67-99% mortality reduction as compared to baseline if high coverage SIAs implemented o 78% reduction in mortality compared to baseline if MCV2 introduced at 18 months in the state with the highest MCV1 coverage; in states with lower MCV1 coverage, the reduction in mortality was 15-35% o Increasing MCV1 coverage had most impact where MCV1 coverage is low o When MCV1 coverage is in the 70-80% range, introducing routine MCV2 is more effective than increasing MCV1 coverage o All methods were cost effective according to WHO standard criteria and SIAs were most cost effective 1) Would a second routine dose have added benefit in the African countries and Cambodia and is an 18 month or 7 year schedule more beneficial? o 87-99% reduction in mortality if routine MCV2 introduced at either age in all examples except DRC, where reduction was 50-70% o Routine MCV2 tended to be more cost-effective at 18 months, but slightly more effective at 7 years due to the assumption of greater independence between doses o MCV2 more or less cost effective in all examples except where MCV1 was very high (95% in Rwanda) 2) Are continued SIAs necessary to maintain elimination in selected Latin American countries? o All countries maintained elimination at a cost savings after stopping SIAs The calculations underlying the fully dynamic model are expected to be more accurate than those of the other two models because the number of predicted cases is estimated by parameters that adjust the risk of infection each week according to seasonality and the population immunity profile in the previous week. However, the model is limited by falsely low age-specific attack rates, which were based on the number of reported cases which is likely a substantial underestimate of actual incidence. The late baseline year (2004) is also problematic because the results capture large epidemics as the epidemic cycles equilibrate that were not included in the other models that had a baseline year of 1980 and hence had more time to equilibrate. Model 2: A cohort component model developed by NIH This model was based on a series of algebraic equations that use age-specific forces of infection that do not vary according to the level of immunity to measles in the population and assume no cases occur over 10 years of age. The model tracks age-specific cohorts through compartments of susceptible, infected, immune, and cause-specific (measles) mortality. 11

12 Key findings 1) What is the best method to accelerate disease control in India? o SIAs have the greatest impact on annual incidence o 40-90% reduction in incidence if MCV2 introduced at 18 months o Increasing MCV1 coverage is important where coverage is low (e.g. 46% in Bihar) o Starting at 74% MCV1 coverage, introducing routine MCV2 is more effective than improving MCV1 coverage o SIAs are more cost effective than other options by over an order of magnitude, despite being the most expensive option 2) Would a second routine dose have added benefit in the African countries and Cambodia and is an 18 month or 7 year schedule more beneficial? o Insignificant benefit associated with introducing routine MCV2 at either age in continued presence of SIAs o MCV2 at 18 months is slightly more effective o Introducing MCV2 would not be cost effective in continued presence of SIAs 3) Are continued SIAs necessary to maintain elimination in selected Latin American countries? o SIAs not needed to contain transmission at high routine and SIA coverage evaluated The calculations in this model are expected to be less accurate than the other models because they do not incorporate seasonality or adjust the force of infection according to the level of population immunity. The results are highly sensitive to the herd immunity threshold, at which point the force of infection (FOI) drops immediately to % of the level used for populations that have not reached herd immunity. Model 3: A cohort component model developed by WHO The Measles Strategic Planning (MSP) Tool is based on a series of algebraic equations in which the force of infection is adjusted according to the proportion of the population susceptible to measles and this relationship is assumed to be the same for all age groups. Key findings 1) What is the best method to accelerate disease control in India? o 85-90% reduction in incidence over baseline when SIAs implemented o Increasing MCV1 coverage is important where coverage is low o Starting at 74% MCV1 coverage, introducing routine MCV2 is more effective than improving MCV1 coverage, but less than 50% as effective as SIAs o All methods are extremely cost-effective and increasing MCV1 coverage to 90% is most cost-effective option 2) Would a second routine dose have added benefit in the African countries and Cambodia and is an 18 month or 7 year schedule more beneficial? o 50-89% reduction in incidence over baseline when MCV2 introduced at 18 months o Even though fewer children are reached at 18 months, an 18 month age of administration is approximately 25-50% more effective than 7 year schedule, except where MCV1 coverage was very low (51% in Equatorial Guinea.) o The cost-effectiveness of introducing MCV2 at either age is roughly around the WHO limit for highly cost-effective interventions for all countries assessed 12

13 Key findings 3) Are continued SIAs necessary to maintain elimination in selected Latin American countries? o Elimination maintained where MCV1 coverage was 98% and MCV2 was 95% (El Salvador), but not maintained in three other countries assessed, where either MCV1 was <90% or MCV2 was <60%. Limitations of the MSP approach are that the calculated incidence rates may be overestimated because the population data are truncated at age 70 years. The MSP approach only projects cases through 2025, so large epidemics at the beginning of the analytical period will have a greater influence on the results than in the other two models. While the herd immunity threshold is critical to the calculations, the results are less sensitive to assumptions regarding herd immunity than in model 2 because the force of infection gradually decreases as immunity increases, rather than immediately dropping to a very small fraction once the herd immunity threshold is reached. Table 2: Summary of differences between models Feature Model 1 (Levin/Burgess) Model 2 (NIH) Model 3 (MSP Tool) FOI determinants Age and contact rates Age Fit distribution based on % susceptible & herd immunity threshold Contact rate determinants Age-specific attack rate, seasonality, & % immune N/A N/A Number of cases within a cohort FOI* % susceptible *population*contact rate FOI*% susceptible* population FOI*% susceptible *population Threshold for herd immunity Importation rate (min. % susceptible) N/A 93.3% 89.5% with periodic pulse Initial immunity and baseline year Set to estimated MCV1 coverage in % in % in 1980 End year Seasonality? Yes- quarterly No No Time step 1 week 1 year 1 year 13

14 Costing for the models The three models used very different costing methods, but produced costs that were within one order of magnitude of each other (Table 3). Costing in the Levin/Burgess model was based on country-level data using a nearest-neighbor approach, whereas the NIH model used global-level average costs adjusted by each country's GNI and the MSP tool used country-level costs for operational expenditures (the largest proportion of routine vaccination costs) and global average costs for all other items. An important limitation of all three models was that they did not use a costing curve that would reflect the higher marginal costs of vaccination that occur at high coverage rates, so the costs per dose at high coverage rates were likely underestimated. Despite these differences and limitations, all models indicated favorable cost-effectiveness for nearly all the vaccination strategies across a variety of scenarios. The WGM felt that costs were overall quite low and that costs and cost-effectiveness should not be overriding concerns when determining vaccination strategies. Table 3: Total cost per dose delivered Levin/Burgess NIH Model MSP Tool El Salvador, MCV1 dose* $1.79 $1.72 $6.87 El Salvador, SIA dose $1.15 $1.27 $0.93 Cameroon, MCV1 dose $0.78 $1.42 $4.24 Cameroon, SIA dose $0.94 $1.04 $0.63 India, MCV1 dose $0.50 $1.36 $2.01 India, SIA dose $0.48 $1.00 $0.45 *Operational costs in El Salvador were expected to average $5.94 per dose delivered in the WHO model. Table 4: Summary of modeling results Question Results 1) For countries with only MCV1 what is the most costeffective strategy to accelerate measles control? 2) What is the added value for a country that is already doing regular SIAs to introduce a 2nd routine dose? 3) For countries with 2 routine doses and SIAs, when is it appropriate to consider stopping SIAs? SIAs most effective regardless of MCV1 coverage Increasing MCV1 coverage is highly cost effective, especially at low MCV1 levels Routine MCV2 effectiveness increases as MCV1 coverage increases All strategies are cost effective Two models support adding routine MCV2 (Levin/Burgess and WHO) Levin/Burgess: moderate reduction in incidence with MCV2 at 7 yrs but slightly less impact with MCV2 at 18 months WHO: moderate reduction in incidence with MCV2 at 18 months; MCV2 at 18m had greater impact than MCV2 at 7yrs WHO: 80% fewer cases with MCV2 at 18 months in countries with high MCV1 (>85%) WHO: MCV2 effectiveness increases as MCV1 coverage increases NIH: no obvious benefit of adding MCV2 at either age Caution in interpreting data as baseline campaign strategy leads to population immunity near herd immunity thresholds where results highly sensitive to assumptions Two models (NIH and Levin/Burgess) showed that SIAs could be stopped while maintaining elimination WHO model found only with MCV1 and MCV2 coverage >95% (e.g., in El Salvador) could SIAs be stopped. More analysis needed to assess MCV1 and MCV2 coverage in the range 80-95% 14

15 Conclusions on modeling Models are always dependent on the input parameters and assumptions which may be based on limited data. This could result in somewhat circular thinking with the model "proving" the underlying assumptions. The following assumptions should be kept in mind when interpreting the model results: Measles vaccine effectiveness: 85% at 9m and 95% at >12m and in SIAs No waning of vaccine-induced immunity MCV1 coverage: WHO/UNICEF estimates MCV2 coverage: as reported by the country (where applicable) SIA coverage: as reported by country in Latin America; 90% elsewhere Rate of increase in MCV2 coverage: linear increase over 5yrs to equal MCV1 coverage MCV2 at 18m: 25% independent of receipt of MCV1 MCV2 at 7yrs: 75% independent of receipt of MCV1 SIA coverage: 100% independent of receipt of MCV1 Homogeneous mixing in the population Homogeneous vaccination coverage Despite their limitations, the models helped to clarify several areas of uncertainty. Firstly, the importance of early administration (e.g., at 18m) of MCV2 to slow the accumulation of susceptibles despite the increased likelihood of revaccinating most children. Secondly, the benefits of delaying MCV2 to school entry age in selective settings - for example where high population immunity has been achieved with MCV1 and near 100% MCV2 coverage can be achieved through school entry checking. Thirdly, that all measles immunization strategies explored were highly cost-effective where the population immunity is low (<90%). Finally, that addition of second routine dose can have a significant impact on population immunity over a broad range of coverage values. This impact is diminished in the presence of high coverage SIAs but does not disappear altogether. 15

16 Analysis subsequent to the January 2009 WGM meeting: Assessing historical experience with the proposed routine MCV2 introduction criteria Despite indications from modeling that countries with 60-80% MCV1 coverage would benefit from the introduction of routine MCV2, the WGM members felt that it was unlikely that countries within this range of MCV1 coverage would be able to achieve high coverage with a second dose delivered through routine services. Subsequent to the January 2009 WGM meeting, country experience with adding routine MCV2 based on preceding MCV1 coverage was analysed. Routine MCV2 coverage in the first five years after introduction was evaluated for two groups: 1) countries with MCV1 coverage in the range 80%-95% during the three years prior to routine MCV2 introduction (n=35) and 2) countries that had at least one year with 60-79% MCV1 coverage during the three years prior to routine MCV2 introduction (n=21). Preliminary findings indicate that although countries with lower starting MCV1 level were able to increase their routine MCV2 coverage during the first 5 years, their performance remained highly variable and their median MCV2 value never reached >90%. By comparison, countries with higher MCV1 starting level were able to achieve consistently a median MCV2 coverage >90% 3-5 years after introduction (Figure 5). An additional analysis found that MCV1 coverage continues to increase after routine MCV2 is introduced, regardless of prior MCV1 coverage, so it appears that MCV2 introduction at any level of immunization system capacity does not threaten maintenance or improvement of MCV1 coverage (see Figure 6.) It was also noted that year-to-year variation in MCV1 coverage tends to be higher among countries with less than 80% MCV1, reinforcing the minimum requirement of three years of 80% MCV1 coverage in order to identify consistently high-performing systems. The proposed criterion for introduction of routine MCV2 (viz., MCV1>80% for 3 consecutive years) appears to appropriately identify countries with better performing immunization systems able to reach high MCV2 coverage. Although countries with MCV1 in the range 60-79% were able to increase their routine MCV2 coverage during the first 5 years, their performance remained highly variable and their median MCV2 value did not reach >90%. MCV2 introduction did not lead to a decrease in MCV1 coverage. 16

17 Figure 5: Routine MCV2 coverage in the first five years after MCV2 introduction, comparing countries that satisfied the proposed criteria (not shaded, n=31) to those that would only have satisfied the criteria if the threshold were 60% (grey shading, n=17)* MCV2 reported coverage Years since MCV2 introduced MCV % x3yrs MCV1 >=60% x3yrs Figure 6: MCV1 coverage in the first five years after routine MCV2 introduction, comparing countries that satisfied the proposed criteria (not shaded, n=35) to those that would only have satisfied the criteria if the threshold were 60% (grey shading, n=21)* MCV1 estimated coverage Years since MCV2 introduced MCV % x3yrs MCV1 >=60% x3yrs *12 countries were excluded because MCV2 was introduced before countries were excluded because MCV1 was over 95% in any of the three years prior to MCV2 introduction, including: Antigua and Barbuda, Argentina, Azerbaijan, Barbados, Belize, Brunei Darussalam, Bulgaria, Canada, Chile, Colombia, Costa Rica, Cuba Dominica, Egypt, El Salvador, Grenada, Hungary, Kuwait, Monaco, Morocco, Oman, Portugal, Moldova, St. Kitts & Nevis, St. Vincent & the Grenadines, San Marino, Sri Lanka, Tonga, USA, and Uruguay. 17

18 Meeting objective #2: Assessing the feasibility of global measles elimination The key areas of work needed to assess the feasibility and appropriateness of global measles elimination were presented (see figure below). The group was reminded that at present, there is no global goal for measles elimination and that the objective of the upcoming work was to enable WHO and the World Health Assembly to make an evidence-based and informed decision about the next global goal for measles control. Most of the work will be contracted out through a request for proposal (RFP) process. The submitted proposals will be selected by an independent expert group (Quantitative Immunization and Vaccine related Research Advisory Committee - QUIVER). The terms of reference and requirements for the proposed economic analysis of measles eradication were presented. The WGM agreed with the approach and recommended the request for proposal for this work be announced as soon as possible (see annex vii) Programmatic feasibility Risk analysis for postmeasles era Biological feasibility Economic analysis Global context and political feasibility Global Consultation Meeting (2010) Recommendations for next measles global goal (2011) Vaccine market analysis Impact on health systems Definition of global measles elimination When the Executive Board (EB) of the World Health Assembly requested the WHO secretariat examine the feasibility of global measles elimination, the term "global measles elimination" was not defined. At the request of the SAGE, the WGM discussed the usage and definition of the terms global measles elimination and measles eradication". The group agreed that global measles elimination means the simultaneous interruption of measles transmission in all countries and regions (i.e., worldwide) as a result of deliberate efforts and that some degree of measles vaccination will continue once interruption of measles virus transmission has occurred. This is in line with the definition of eradication, except that the current definition of eradication includes the phrase "no further intervention is necessary". In addition, the current definition of disease elimination specifies that intervention measures must be continued as would be the case with global measles elimination. The WGM felt that eradication is technically the correct term to describe worldwide interruption of measles transmission, However, many participants expressed concern that the term "eradication" was too closely associated with current polio eradication efforts that involve complex post-eradication scenarios to manage the risk of vaccine-associated disease and the need for laboratory containment of polioviruses. The WGM felt that use of the term "global measles elimination" may be more appropriate because it reflects the public health goal of stopping transmission worldwide with limited need for virus containment because vaccination would be continued after elimination is achieved. 18

19 Annexes: I. Report on the 1 st Meeting of the SAGE WGM II. Report on the 2 nd Meeting of the SAGE WGM III. Wkly Epid Record, 12 January 2007, 82:1-16. IV. Wkly Epid Record, 9 January 2009, 84:1-16. V: List of participants VI. Meeting Agenda, 3 rd Meeting of the SAGE WGM VII. Request for proposal -- The cost-effectiveness of measles eradication vs. control 19