# In a nutshell

This page discusses supplementary immunization activities (SIAs) to prevent illness caused by the measles virus. Measles is a highly infectious airborne virus which can be deadly to children under five years of age. SIAs include mass immunization campaigns, follow-up campaigns, outbreak response, and supporting activities such as vaccine coverage surveys and case surveillance.

We find it plausible that SIA campaigns targeted at children under five years old may be as cost-effective as our priority programs. However, since Gavi significantly increased its funding for measles immunization work in December 2015, we do not believe that there is significant room for more funding to support these campaigns. We believe that there may be funding gaps to vaccinate children over five years old, but our best guess is that these activities are not as cost-effective as our priority programs.

We continue to be interested in this space, but we have deprioritized further work after learning of Gavi's increase in funding for measles work. Our last substantive inquiry into measles SIAs was in January 2016.

Published: August 2017

## What is the problem?

Measles is a highly contagious airborne viral disease. Symptoms include high fever, runny nose, bloodshot eyes, and tiny white spots on the inside of the mouth, followed by a characteristic rash.1 Those infected may develop complications such as pneumonia and diarrhea, and may rarely develop serious complications such as encephalitis and blindness.2 The disease can be fatal, especially to children under five years of age (more).

The Americas have eliminated measles.3 However, the World Health Organization (WHO) estimates that over 20 million people are affected by measles each year, primarily in the South-East Asia Region, Western Pacific Region, and African Region.4 In 2014, WHO estimated that more than 60% of the estimated 21.5 million children who were not vaccinated against measles at 9 months of age in the previous year came from six countries: India, Nigeria, Pakistan, Ethiopia, Indonesia, and the Democratic Republic of Congo.5 According to WHO, more than 95% of measles deaths occur in countries with low per capita incomes and weak health infrastructures.6

### Estimated deaths

As reported data on measles deaths is generally not available, WHO uses mathematical models to estimate both the true incidence rate of measles and, using observed or estimated rates of death among infected people, deaths due to measles.7 WHO estimates 2015 global measles deaths at 134,200, of which 46% were in the African region and 41% were in the South East Asia region.8 WHO reports estimated measles deaths by year and region, but we have not found country-specific estimates of deaths.

### Mortality and age at infection

Age at infection is an important factor in the mortality of measles. It is our impression that the risk of dying from measles is widely considered to drop significantly beyond age five.9 In this report, we focus on mortality of children under five. Based on limited evidence, almost all age classes under five years exhibit a decreasing trend in mortality with each additional year, though mortality rates appear to be very similar for children 0-11 months and 12-23 months old.10

## What is the program?

In this report, we focus on prevention of measles deaths via supplementary immunization activities (SIAs). SIAs include mass immunization "catch-up" campaigns targeting a wide age range (typically 9 months to 14 or 15 years of age), "follow-up" campaigns targeting children who have aged past the 9-month mark since the previous campaign and scheduled at 2-4 year intervals based on the epidemiological conditions of the region,11 smaller "mop-up" campaigns targeting specific groups or subregions missed by a previous campaign, and emergency mass immunizations during outbreaks. SIAs aim to provide every child with a first or second dose of measles vaccine. Because of the chance of previous vaccine failure (more), SIA catch-up campaigns generally target all children regardless of vaccination history.12 SIAs are credited in past successes of measles control.13

SIAs are part of a broader integrated approach to measles control and elimination, which includes routine immunization, disease surveillance, public communication, and research.14

## Who is working on it?

The Measles and Rubella Initiative (M&RI) is a global partnership of organizations (including WHO and UNICEF)15 supporting the control and eventual eradication of measles. M&RI is the funding vehicle through which national governments apply for co-funding of measles supplementary immunization activities,16 and hence it is our understanding that M&RI is the vehicle through which individual donors could contribute funds to measles immunization in high-need countries. M&RI estimates that its 2015-2020 activities in 77 priority countries will total $2.6 billion.17 When M&RI funding for measles campaigns is not available, campaigns may run with fewer support activities, be reduced in scale, or be delayed.18 National governments plan and carry out SIAs with technical and financial support from international agencies.19 National governments are generally expected to cover about 30-50% of the operational costs of follow-up SIAs.20 Gavi, the Vaccine Alliance, a large funding vehicle for vaccinations, had previously pledged$600 million for measles and rubella vaccination for 2016-2020. In December 2015, Gavi announced that it was increasing this pledge by $220 million.21 Gavi's funding primarily supports measles immunization campaigns targeting children under five years of age in eligible countries.22 In 2016, 54 countries were eligible for support from Gavi funds.23 As of January 2016, M&RI was aiming to secure funding for immunization of older children, for campaigns in 25 priority countries not eligible for Gavi funding,24 and for its support activities.25 ## Does the program work? We are confident in the evidence that measles vaccination is at least 95% effective in preventing measles cases when administered after 15 months of age, and that vaccine efficacy decreases with age below 15 months. We have incomplete information regarding the extent to which SIAs reach unimmunized persons, but evidence from past campaigns suggests significant drops in measles incidence following many SIAs. ### Does the vaccine work? There is wide consensus that the measles vaccine is effective26 and safe.27 MR (measles and rubella) or MMR (measles, mumps, and rubella) vaccines are increasingly used in developing countries instead of the measles-monovalent (called M or MV) vaccine, though the MV vaccine is still widely used.28 According to WHO, combining measles vaccination with other vaccine components such as rubella, or mumps and rubella, does not reduce its effectiveness.29 We have not reviewed evidence about the comparative effectiveness of monovalent and combination vaccines, and our evidence for vaccine effectiveness comes from studies of MMR effectiveness, but our impression is that this is not controversial. Measles vaccination is less effective in infants due to the inhibitory effect of maternal antibodies.30 Based on two reviews of vaccine efficacy studies, the measles vaccine is generally considered to be about 85% effective when administered at 9 months.31 Based on a Cochrane review of three cohort studies, the vaccine is generally considered 95% effective when administered after 12 months of age.32 In infants, vaccine effectiveness may show variance based on dosage and strain;33 among children without maternal antibody protection, vaccine effectiveness does not appear to vary based on dosage or strain.34 Vaccine effectiveness does not appear to increase with age beyond 15 months.35 Studies indicate that immunity to measles following vaccination lasts for decades and may be boosted by subsequent exposure to the virus.36 Measles vaccines have reduced efficacy when refrigeration ("cold chain") is not maintained,37 and in individuals infected with HIV.38 ### Do SIAs reach unimmunized people? In this section we address how many people receive measles vaccination prior to SIA vaccination and whether SIAs can reach populations which have limited contact with health systems. We are uncertain to what extent SIAs reach unimmunized people. There is available data of mixed quality on how many people are immunized through routine services prior to being reached by an SIA; we believe that SIAs reach more unimmunized people in areas with low routine coverage. We have found little high-quality information on whether or how SIAs specifically target populations that are more likely to be unimmunized. #### Routine immunization Vaccine delivery through government health programs is referred to as routine immunization. Balancing the higher risk of mortality at younger age of infection with the higher risk of vaccine failure at younger age of vaccination, most national health programs in developing countries vaccinate children at 9 months of age.39 This first measles vaccination is referred to as MCV1 (Measles Containing Vaccine 1). Some countries also deliver a second, later dose of measles vaccine (MCV2) through routine services.40 SIAs tend to target countries with little or no MCV2 coverage.41 There is a great deal of data available regarding routine immunization coverage. WHO collects administratively reported MCV1 and routine MCV2 coverage data from countries, and also produces estimates of routine coverage.42 In 2015, 75 countries were estimated to have MCV1 (which is delivered via routine immunization) coverage below the 2015 target of 90%, 26 below 70%, and 4 below 50%. South Sudan had the lowest estimated coverage rate at 20%.43 SIAs are more likely to reach unimmunized persons in regions with low MCV1 coverage. While many concerns arise when evaluating the accuracy of reported coverage data and applicability of estimation methods,44 the WHO/UNICEF estimated coverage rates are the source of our best guess at current national MCV1 and routine MCV2 coverage. #### Studies of SIA reach We have found two studies of the extent to which SIAs reach unimmunized people or populations less likely to be reached by routine services. We have not reviewed these studies in detail, or searched thoroughly for additional studies. SIA Year Region Study Size Result Reference 2002 Kenya (nationwide) 1455 children aged 9–23 months Analysis of a post-SIA Kenya Ministry of Health national coverage survey found that the SIA improved coverage in the poorest two wealth quintiles.45 Vijayaraghavan et al. 2007 1998 Burkina Faso (Ouagadougou and Bobo Dioulasso, largest two cities) 1041 children aged 9-59 months A post-SIA cluster survey found that 78% of children not previously vaccinated were reached by the SIA, and that the education levels of caregivers predicted MCV1 vaccination, but not SIA vaccination.46 Zuber et al. 2001 ### SIA coverage rates SIAs are often estimated to reach about 95% of their target population. Challenges to achieving high SIA coverage rates include population movements, isolated populations, and opposition to vaccination.47 We rely on three sources of evidence about SIA coverage: (1) coverage administratively reported as number of vaccines delivered divided by estimated target population, (2) coverage extrapolated from post-SIA surveys and reported to WHO, and (3) academic studies of coverage surveys. We believe there are serious limitations to the quality of administratively reported coverage and post-SIA surveys. Of the three academic studies of SIA coverage we have found, only one adequately discusses survey methodology. Despite the limitations of the data on SIA coverage rates, we believe that SIA campaigns can in fact achieve very high coverage. The best evidence for this comes from studies of decline in cases and outbreaks after SIAs (more). #### Administratively reported SIA coverage Since 2000, WHO has compiled reported SIA coverage rates measured as the number of vaccine doses reported delivered to individuals in the target population divided by the estimated size of the target population.48 We are uncertain about the completeness of this dataset. Of 1065 SIAs recorded as "done" in 2000-2017, 54 (5%) have no administratively reported coverage, 30 (3%) have reported coverage <10%, and 197 (18%) have reported coverage >100%. Median reported coverage is 95%.49 WHO notes that many SIA campaigns reporting 95% overall coverage do not meet the WHO target of 95% coverage in every district.50 Due to known administrative data collection and reporting challenges, we are not confident in the accuracy of reported SIA coverage rates.51 #### Post-SIA coverage surveys The WHO SIA coverage dataset52 comparatively notes, where applicable, coverage estimates based on post-SIA surveys. Several types of surveys are used in assessing SIA coverage.53 Of 1065 SIAs recorded as "done" in 2000-2017, 60 (6%) are marked as having an SIA survey, and 58 report the coverage found by an SIA survey.54 Post-SIA surveys often find lower coverage rates than are administratively reported.55 Among SIAs reporting coverage survey results, the mean administratively reported coverage was 98.35% and the mean coverage found in surveys was 90.86%.56 We do not take mean coverage found in surveys to be indicative of mean SIA coverage; it seems plausible that SIAs which include coverage surveys are not representative of SIAs generally. Furthermore, a review of the methodology of the 13 surveys conducted in eastern and southern Africa following 2012-2013 SIAs found serious methodological gaps and concerns.57 #### Published studies of SIA coverage The table below presents the few journal-published studies of SIA coverage we have found. While these studies of SIA coverage provide data independent from campaign-reported coverage rates, the researchers are generally affiliated with WHO and/or national governments. We have not reviewed these studies in detail. SIA Year(s) Region Study Size Results Reference 2002 Kenya (nationwide) 1455 children aged 9–23 months A national household coverage survey found that the caretakers of 83% of children 9-23 months of age could produce cards distributed during the SIA as proof of vaccination.58 Vijayaraghavan et al. 2007 2001-2002 Afghanistan (Kabul, largest city) 3537 children aged 6mo-12yrs Coverage in Kabul city was administratively reported as 62%, possibly resulting from a population overestimate. A cluster survey found 91% coverage among children 6mo-5yrs, and 88% among children 5-12yrs of age.59 Dadgar et al. 2003 1998 Burkina Faso (Ouagadougou and Bobo Dioulasso, largest two cities) 1041 children aged 9-59 months Cluster surveys conducted one week after National Immunization Days found that 79% of surveyed children 9-59 months of age were vaccinated in the SIA.60 Zuber et al. 2001 ### Do SIAs reduce measles incidence? We use two approaches to investigate the extent to which measles incidence is reduced following an SIA: trends in administratively reported cases and local studies of incidence. We believe that historical trends in measles cases before and after SIAs provide the strongest evidence that SIAs can drastically reduce measles incidence. However, it appears that SIAs do not always significantly reduce measles case rates or prevent outbreaks. We do not have a good understanding of what factors lead to SIA effectiveness or ineffectiveness in reducing cases. #### Broad trends in case reduction following SIAs In many countries, SIAs have been overwhelmingly successful in reducing or nearly eliminating measles transmission. The effect of SIAs can be observed by comparing a country's measles incidence trend with its routine immunization trend and the timing of SIAs. Three major factors complicate the attribution of trends in measles cases: 1. A country's first large national catch-up SIA often coincides with a change in reporting practices. 2. Initiating regular SIA campaigns in a country often coincides with increasing MCV1 coverage.61 3. SIAs (both large catch-up campaigns and smaller follow-ups) sometimes coincide with outbreaks and the drops in incidence which follow due to acquired immunity. Examples of successes. In the Americas, mass immunization catch-up campaigns were instrumental in reducing reported yearly cases from >250,000 in 1980 to zero in 2003.62 In southern Africa, a vaccination strategy including routine immunization, mass catch-up SIAs, and regular follow-up SIAs in six countries reduced reported measles incidence from 60,000 cases in 1996 to 117 cases in 2000, although >1,200 cases were recorded in 2002-2003 outbreaks.63 Measles cases also significantly declined (89% average reduction) following SIAs in 12 eastern and western African countries in 2000-2003.64 In Ethiopia, reported measles cases declined 93% from 1999-2002 to 2003-2005 after a large national catch-up campaign in 2003-2004.65 Ambiguous examples. In some countries, the effect of SIAs on reported measles cases is unclear or confounded by concurrent events such as outbreaks or increases in routine vaccine coverage. We do not have a good understanding of what factors cause SIAs to have large effects on measles case rates.66 Examples of ineffective SIAs. In some cases, SIAs fail to reduce measles incidence. An outbreak in Malawi in 2010 comprised 134,000 cases and 304 deaths; survey-reported SIA coverage for the 2008 SIA was 60.7%.67 #### Local studies of case reduction following an SIA We have found few retrospective studies of measles incidence rates before and after SIAs which do not rely on administrative data. The three studies we have found are summarized below. Two of these studies (in Nigeria and South Africa) appear to demonstrate a positive effect of SIAs. However, in one study (in Viet Nam), it appears that SIAs were ineffective at preventing outbreaks and at protecting their targeted age populations from infection. SIA Year(s) Region Results Reference 2006-2010 Ilesa, Nigeria Examination of the admittance records of the Wesley Guild Hospital in Ilesa, Nigeria from 2001-2010 found 4.3% admittances due to measles complications prior to the SIA campaign (2001-2005), and 0.6% during the SIA period (2006-2010); an average of 44.4 complicated measles cases averted per year.68 Peter, Ademola, and Oyeku 2014 1999-2004, 2007-2008 Viet Nam A review of surveillance data from Expanded Programme on Immunization forms and forms submitted by four regional measles laboratories investigating the outbreaks which occurred in 2008 through January 2010: In 5 out of 22 provinces which had conducted SIAs in 2007-2008, measles incidence was unexpectedly high. In the two provinces whose SIA target population was 9mo-20yrs old, 54% of 233 confirmed cases occurred in the age range targeted by SIAs. In the three provinces whose SIA target population was 6-20yrs old or 7-20yrs old, 34% of 549 cases occurred in the targeted age range. Reported coverage of SIAs in almost all provinces had been ≥95% since 2002.69 Sniadack et al. 2011 1996-1997 Mpumalanga and Western Cape provinces, South Africa A review of the records of participating hospitals in two provinces of South Africa compared cases recorded in the 5-6 years prior to SIA campaigns (1992-1996/7), and 1-2 years immediately after SIA campaigns (1997-1998, 1998). In predominantly rural Mpumalanga, average annual measles-related hospitalizations declined from 329 to 29, and all 11 deaths occurred before the SIA (0.7% case-fatality ratio). In predominantly urban Western Cape, average annual incidence declined from 123 to 20 cases in 1998, and all 23 deaths occurred before the SIA (3.1% case-fatality ratio).70 Uzicanin et al. 2002 ## How much does the program cost? In this section, we consider the cost of conducting an SIA as the sum of vaccine cost, operational cost, and "core" operational costs incurred by international partners.71 As a ballpark estimate, we believe that a typical measles SIA incurs a per-person cost of <$0.50 for the vaccine, <$2.00 in operational costs, and <$0.20 for operational support, for a total of <$2.70 per person vaccinated. However, the operational cost per person may vary greatly based on characteristics of the population, country infrastructure, environment, and economies of scale. Throughout this page, we report costs in 2015 USD.72 ### Vaccine Prices UNICEF publishes awarded prices for vaccines.73 Price per dose of measles monovalent vaccine varies by supplier from$0.2250-$0.4750 in 2015 and$0.2271-$0.4938 in 2016.74 MR vaccines cost$0.5780 per dose in 2015 and $0.5985 per dose in 2016.75 MMR vaccines cost$1.0770-$3.2500 per dose in 2015 and$1.1159-$3.2095 per dose in 2016.76 UNICEF also publishes historical procurement data (volume and value).77 UNICEF procured 295.6 million measles-containing vaccines (57% M, 38% MR, 5% MMR) in 2015 at an average price of$0.43 per dose.78

Vaccine costs in measles SIAs are usually covered by international partners such as the Measles and Rubella Initiative or Gavi.79

### SIA operational expenses

The data set from Gandhi and Lydon 2014 (a review of three types of data on in-country SIA operational expenses) is our best source of country-specific operational cost estimates, consisting of 41 country expenditure reports, 10 SIA budgets, and 13 estimates from the literature. This review is limited by paucity of data, non-standardized reporting, and a reporting bias towards countries involved in the Gavi program and countries in the African region.80 The latter is not a concern for our purposes, as many countries in which we expect future measles SIAs to take place are Gavi-eligible countries in the African region.

Analysis of 38 country-specific measles comprehensive Multi-Year Plans (cMYPs) submitted to WHO/UNICEF in 2009 and 2011 and representing 30 countries81 indicates a weighted average operational expenditure of $0.88 per person.82 Regionally, average operational costs per person were$1.28 in the WHO African Region, $0.78 in the South-East Asian Region, and$0.36 in the Eastern Mediterranean Region.83

A review of ten measles SIA budgets (all from 2009-2011) indicates operational costs per person ranging from $0.22-$2.49 (mean $0.88, median$0.66).84

A literature review seeking primary data on SIA cost estimates and expenditures85 identified five papers on operational costs of nine measles-only SIAs, and three additional papers addressing four measles-including integrated SIAs. Nine of these campaigns were examined retrospectively, and four had unspecified perspective. Year of cost data ranged from 2000-2009. Literature-estimated operational cost of measles-only SIAs ranged from $0.030-$0.746 per dose; the four integrated campaigns ranged from $0.177-$0.368 per dose.86 When comparable data was available, country plans generally reported higher costs than literature-published estimates.87

The retrospective budget available in the Measles and Rubella Initiative Annual Report 2014 (p. 44) presents budget categories differently than the Financial Resources Requirements report. Of the $43 million that M&RI reports spending in 2014, 33% ($14.19 million) was spent on SIA operations and 6% ($2.58 million) on technical assistance. We are uncertain about how to reconcile the differences between these two financial reporting documents. ## What do you get for your money? We believe it is likely that well-run measles vaccination campaigns targeting children under five years of age in priority areas91 are potentially as cost-effective (in terms of cost per death averted) as our priority programs (see our very rough cost-effectiveness model in the following footnote).92 We believe that targeting older children in mass immunization campaigns is likely less cost-effective than our priority programs, partly because mortality due to measles seems to occur primarily in the under-five age group. We have not thoroughly investigated the relative cost-effectiveness of programs targeted at these age groups, but have not seen compelling evidence that targeting a broader age group is cost-effective.93 Based on a conversation with the Measles and Rubella Initiative, we believe that there is room for more funding for immunization campaigns targeting children over five years old, but not for campaigns targeting children under five years old.94 ### Targeting children under five It is our understanding from the literature that mortality due to measles primarily occurs in children under five years of age. We have come to this understanding based on the following: • We believe that we have done a fairly comprehensive search of the measles literature and have seen very little discussion of measles mortality in older age groups. • In order to estimate the global burden of measles, WHO focuses on measles mortality rates in children under five. WHO estimates that in low-income countries, between 0.05% and 6% of measles cases in children under five result in death; in complex emergencies or in isolated areas where there is low natural immunity or low vaccination coverage, this estimate can be as high as 10-30%.95 • Estimates from the GBD Compare tool (see GBD Compare - total measles deaths) suggest that about 85% of global measles deaths in 2015 were among children under five.96 These estimates are presented with large uncertainty intervals, especially for deaths in children under five. We have not vetted these estimates. Because measles deaths occur primarily in children under five, our back-of-the-envelope model of the cost-effectiveness of measles immunization campaigns estimates that expanding the age range of a campaign to include older children increases the cost of the campaign but does not similarly increase the number of deaths averted. Gavi, a large vaccine funding vehicle, prioritizes measles funding for children under five years of age. It is our understanding that Gavi generally does not fund measles vaccination for children over five in follow-up campaigns (i.e. campaigns beyond the first large national campaign in each country).97 We take the fact that Gavi deprioritizes measles vaccination campaigns for children over five relative to its other vaccination funding opportunities as some evidence that these activities are unlikely to have cost-effectiveness competitive with that of our priority programs. ## Is there room for more funding? As discussed above, we believe that vaccination of children under five years of age is the measles supplementary immunization activity most likely to have comparable cost-effectiveness to that of our priority programs. It seems likely to us that any gaps that may arise for vaccinating this age group will be filled by Gavi and/or M&RI, since both organizations prioritize vaccinations for this population. As of October 2015, the Measles and Rubella Initiative projected a funding gap of$431 million for 2015-2020.98 As of our last conversation with M&RI in January 2016, it was working on updating its estimate of its 2016-2020 financial resource requirements following Gavi's December 2015 announcement of its commitment to provide an additional $220 million in support for measles activities. At this point, M&RI estimated that the new Gavi commitment might close the 2016-2020 funding gap by approximately$130 million, leaving a funding gap of about $300 million.99 Since we expect M&RI to use this additional funding to support programs for children under five, which we see as the most cost-effective funding gap, it seems likely to us that the remaining funding gap would be less cost-effective than our priority programs. We have not asked M&RI for an updated estimate of its funding gap since January 2016. It is possible that upon further investigation we might find remaining funding gaps for SIAs targeting children under five, although we believe this is unlikely. We have also not confirmed whether there are any countries or territories with significant measles burden, low rates of routine immunization, and high rates of measles fatality that are not included in M&RI or Gavi's lists of priority countries. It is possible that this has caused us to overlook opportunities to fund measles SIAs in neglected areas, though we believe this to be unlikely. ## What are our biggest remaining questions? • Are there any funding gaps for vaccination of children under five in the next few years? • Are there countries or regions with a need for measles support that is not met or recognized by M&RI? • What is the state of the evidence on effects of measles SIAs targeting older children on measles mortality? • What is the state of the evidence on effects of measles SIAs in M&RI priority countries on long-term measles control and cost savings? • If M&RI had a large amount of additional funding, could it run additional cost-effective campaigns? Or is the campaign schedule constrained by epidemiological considerations? • Could additional money contributed to under-five campaigns increase the coverage of these campaigns in a cost-effective way? ## Our process We began investigating measles supplementary immunization activities due to our impression that they could be in the same range of cost-effectiveness as our priority programs. In January 2016, after Gavi's increase in funding for measles, we discussed room for more funding with the Measles and Rubella Initiative. We have deprioritized the investigation after learning that it seems unlikely that there will be room for more funding for vaccination of children under five in the near future. ## Sources Document Source Anders et al. 1996 Source (archive) Bishai et al. 2010 Source (archive) Castillo-Solorzano et al. 2011 Source (archive) CDC Pinkbook: Measles Source (archive) CDC, Progress Toward Regional Measles Elimination — Worldwide, 2000–2015 Source (archive) Cutts, Grabowsky, and Markowitz 1995 Source (archive) Dabral 2009 Source (archive) Dadgar et al. 2003 Source (archive) Dayan et al. 2003 Source (archive) Demicheli et al. 2012 Source (archive) Gandhi and Lydon 2014 Source (archive) Gandhi and Lydon 2014 Additional files (xlsx) Source (archive) Gavi board decisions, December 2015 Source (archive) Gavi December 2015 press release Source (archive) Gavi website, "Gavi pledging conference June 2011" Source (archive) Gavi website: Countries eligible for support Source (archive) Gavi website, "World leaders make record-breaking commitment to protect poorest children with vaccines" Source (archive) Gavi's measles and rubella strategy, report to the board, December 2015 Source (archive) GBD Compare - total measles deaths Source (archive) GiveWell's interim cost-effectiveness analysis of measles SIAs Source GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016 Source Hoekstra et al. 2011 Source (archive) Kaiser et al. 2015 Source (archive) Ladapo et al. 2013 Source (archive) Levin et al. 2010 Appendix Source (archive) Levin et al. 2011 Source (archive) Measles Strategic Planning (MSP) Tool, xls 35.31 Mb Source (archive) Measles and Rubella Initiative Annual Report 2013 Source (archive) Measles and Rubella Initiative Annual Report 2014 Source (archive) Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015 Source (archive) Measles and Rubella Initiative website: founding partners Source (archive) Minetti et al. 2013 Source (archive) Otten et al. 2003 Source (archive) Otten et al. 2005 Source (archive) PAHO website fact sheet, Measles elimination in the Americas Source (archive) Perry and Halsey 2004 Source (archive) Peter, Ademola, and Oyeku 2014 Source (archive) SAGE 2014 Assessment Report of the Global Vaccine Action Plan Source (archive) SAGE 2015 Assessment Report of the Global Vaccine Action Plan Source (archive) Scott et al. 2011 Source (archive) Simons et al. 2011 Source (archive) Simons et al. 2012 Source (archive) Simons et al. 2012 Appendix Source (archive) Sniadack et al. 2011 Source (archive) Sudfeld, Navar, and Halsey 2010 Source (archive) UNICEF Vaccine Procurement (Value) Source (archive) UNICEF Vaccine Procurement (Volume) Source (archive) UNICEF MCV Supply Update 2013 Source (archive) UNICEF Vaccine Price Data Source (archive) UNICEF Vaccine Price Data (Measles) Source (archive) UNICEF Vaccine Price Data (MR) Source (archive) UNICEF Vaccine Price Data (MMR) Source (archive) US Inflation Calculator Source (archive) Uzicanin et al. 2002 Source (archive) Uzicanin et al. 2004 Source (archive) Uzicanin and Zimmerman 2011 Source (archive) Vijayaraghavan et al. 2006 Source (archive) Vijayaraghavan et al. 2007 Source (archive) WHO/UNICEF Estimates of National Immunization Coverage by country (1980-2015) (Excel 492kb) Source (archive) WHO/UNICEF Estimates of National Immunization Coverage (Country Summaries) Source (archive) WHO/UNICEF Estimates of National Immunization Coverage (Methods) Source (archive) WHO/UNICEF Estimates of National Immunization Coverage by country (1980-2015) (HTML) Source (archive) WHO Africa Measles Field Guide 2010 Source (archive) WHO Data and statistics web page Source (archive) WHO Global measles and rubella strategic plan, 2012-2020 Source (archive) WHO Measles reported cases by country (1980-2016) (HTML) Source (archive) WHO Measles reported cases by country (1980-2016) (Excel 566kb) Source (archive) WHO Measles reported MCV1, MCV2 coverage by country (1980-2016) (HTML) Source (archive) WHO Measles reported MCV1, MCV2 coverage by country (1980-2016) (Excel 602kb) Source (archive) WHO Measles surveillance data, May 2017 Source (archive) WHO Measles surveillance web page Source (archive) WHO Measles vaccine web page Source (archive) WHO Measles web page Source (archive) WHO Module 7: Measles, 2009 Source (archive) WHO news release, Nov. 2014 Source (archive) WHO Progress towards measles pre-elimination, African Region, 2011–2012 Source (archive) WHO raw monthly administrative coverage data by country (2000-2016) (Excel 21.5Mb) Source (archive)100 WHO Reported Measles Cases by Region, 2016, 2017 Source (archive) WHO routine coverage survey data (1980-2015) (Excel 5.0Mb) Source (archive)101 WHO Strategies to reduce measles mortality Source (archive) WHO Summary of Measles SIAs 2000 to 2017 (Excel 290kb) Source (archive)102 WHO Vaccine Reactions Information Sheet Source (archive) WHO Weekly Epidemiological Record 2 April 2004 Source (archive) WHO Weekly Epidemiological Record 4 March 2005 Source (archive) WHO Weekly Epidemiological Record 11 November 2016 Source (archive) Wolfson et al. 2009 Source (archive) Zhou et al. 2011 Source (archive) Zuber et al. 2001 Source (archive) • 1. "Measles is transmitted via droplets from the nose, mouth or throat of infected persons. Initial symptoms, which usually appear 10–12 days after infection, include high fever, a runny nose, bloodshot eyes, and tiny white spots on the inside of the mouth. Several days later, a rash develops, starting on the face and upper neck and gradually spreading downwards." WHO Measles web page. • 2. "Those unvaccinated against the disease are at risk of severe health omplications [sic] such as pneumonia, diarrhoea, and encephalitis (a dangerous infection of the brain causing inflammation) and blindness. The disease can be fatal." WHO Measles web page. • 3. "In 2016, an international expert committee reviewed the epidemiological evidence presented by the member countries of the Pan American Health Organization/World Health Organization (PAHO/WHO) and determined that the Region of the Americas had eliminated endemic transmission of measles. This was announced at the 55th Directing Council of PAHO in September 2016." PAHO website fact sheet, Measles elimination in the Americas. • 4. • "Indeed, more than 20 million people are affected by measles each year." WHO Measles web page. • Of cases reported and confirmed as measles in 2016, 42% were in the South-East Asia Region, 30% in the Western Pacific Region, and 19% in the African Region. WHO Reported Measles Cases by Region, 2016, 2017, calculated from column "Total measles". • 5. "More than 60% of the estimated 21.5 million children who were not vaccinated against measles at 9 months of age last year came from 6 countries: • India (6.4 million) • Nigeria (2.7 million) • Pakistan (1.7 million) • Ethiopia (1.1 million) • Indonesia (0.7 million) • Democratic Republic of Congo (0.7 million)" • 6. "The overwhelming majority (more than 95%) of measles deaths occur in countries with low per capita incomes and weak health infrastructures." WHO Measles web page. • 7. • "Because most measles deaths are in countries where vital registration systems cannot provide reliable information on cause-specific mortality, WHO has relied on mathematical models to estimate the global burden of measles." Simons et al. 2012, p. 2173 (p. 1 of pdf). • "The MSP [Measles Strategic Planning] tool estimates measles incidence and mortality through a country-specific cohort model, using a probability of infection dependent on population immunity levels. This method approximates measles transmission dynamics without requiring detailed data that would prohibit use in low- and middle-income countries. Coupled with cost data, the tool estimates incremental costs and cost effectiveness of user-defined vaccination strategies over 5–10 year planning periods." Simons et al. 2011, p. S28. • "Deaths are calculated by applying an age and country-specific CFR [case-fatality ratio] to infections." Simons et al. 2011, p. S31. • The Measles Strategic Planning (MSP) tool is available for download at the bottom of the WHO Strategies to reduce measles mortality web page. We have not examined it in detail. • Simons et al. 2012 presents a new state-space modeling method. We are uncertain which modeling method is currently used by WHO. "State-space models are valuable tools for disease burden estimation because they provide a probabilistic framework to predict the unobserved outcome of a dynamic process, such as true measles incidence, given observed elements of that dynamic process, such as reported measles cases and vaccination coverage. In addition to providing an objective method for interpreting surveillance data, the state-space model offers a formal method for estimating uncertainty in the unobserved burden that is derived directly from the observed surveillance data, rather than from ad hoc bounds on model parameters as has been done previously." Simons et al. 2012 Appendix, p. 5. • 8. Table 2, WHO Weekly Epidemiological Record 11 November 2016, p. 531. • 9. Some sources report that death and complications are more common in children under five and adults over twenty (e.g. "Complication rates are higher in those <5 and >20 years," Perry and Halsey 2004, p. S4). However, this appears to be based on data from measles complications in the United States, 1987–2000, which shows 97 deaths under 5 (0.3% case-fatality ratio (CFR)), 26 deaths aged 20-29 (0.3% CFR) and 27 deaths over age 30 (0.7% CFR) (ibid. Table 2). We have not found studies of measles CFRs in adults in developing countries (where CFRs for children under five are often 1-6%), and in the literature there is little focus on over-five mortality. • 10. "Few studies employed age groups refined enough to estimate CFR [case-fatality ratio] by single years of age for children under 5 years of age. Even fewer studies addressed case fatality in infants (age 0–11 months). Of the studies (n=10) that allowed for the analysis of CFRs for children under 5 years of age, the age-specific CFR varied considerably by age class but almost all exhibited a decreasing trend with each year increase in age. A slightly different pattern is seen, however, when the data are aggregated across studies (Figure 2), particularly in comparing the CFR for children 0–11 months and 12–23 months." Wolfson et al. 2009, pp.199-200. Figure 2 shows very similar median CFRs for these two youngest age groups, with a slightly higher median CFR for the older age group. • 11. • "A schedule of SIAs is projected over several years based on routine coverage and the quality and coverage of previous SIAs." Measles and Rubella Initiative Annual Report 2013, p. 44. • "The interval between follow-up SIAs is determined by epidemiological analysis, including coverage rates, the age distribution of cases, and the estimated rate of accumulation of susceptible children. These non-selective SIAs not only give a second dose to children reached by the vaccination programme but also ensure that missed children are protected, especially those in poor or hard-to-reach communities." WHO Global measles and rubella strategic plan, 2012-2020, p. 21. • 12. "Supplemental Immunization Activities (SIAs), also referred to as mass immunisation campaigns, are necessary to reach never‐vaccinated children who have never had measles disease and to provide an opportunity for a second dose for cases of primary vaccine failure. All children in the target age group and geographic area will be eligible to receive a dose of measles vaccine irrespective of past immunisation or history of clinical measles." WHO Africa Measles Field Guide 2010, p. 10. • 13. "In 2000, the World Health Assembly adopted a resolution to reduce global measles deaths by half compared with 1999 levels, from 2000–2005. This goal was achieved globally following the implementation of a five-year strategic plan to increase coverage with measles vaccination through routine immunization and SIAs." WHO Global measles and rubella strategic plan, 2012-2020, p. 14. • 14. • The goals and milestones listed in the WHO Global measles and rubella strategic plan, 2012-2020 include (p. 13): • By the end of 2015: • "Reduce global measles mortality by at least 95% compared with 2000 estimates." • "Reduce annual measles incidence to less than five cases per million and maintain that level. • Achieve at least 90% coverage with the first routine dose of measles-containing vaccine...nationally, and exceed 80% vaccination coverage in every district or equivalent administrative unit. • Achieve at least 95% coverage with M [measles], MR [measles and rubella] or MMR [measles, mumps, and rubella] during supplementary immunization activities (SIAs) in every district." • By the end of 2020: • Achieve measles elimination in at least 5 of the 6 WHO regions. • "Sustain the achievement of the 2015 goals. • Achieve at least 95% coverage with both the first and second routine doses of measles vaccine...in each district and nationally." • The plan presents a five-fold strategy for measles control and elimination (p. 20). "The five components of the strategy are: 1. Achieve and maintain high levels of population immunity by providing high vaccination coverage with two doses of measles- and rubella-containing vaccines. 2. Monitor disease using effective surveillance and evaluate programmatic efforts to ensure progress. 3. Develop and maintain outbreak preparedness, respond rapidly to outbreaks and manage cases. 4. Communicate and engage to build public confidence and demand for immunization. 5. Perform the research and development needed to support cost-effective operations and improve vaccination and diagnostic tools." • 15. See Measles and Rubella Initiative website: founding partners, which describes the roles of the five founding partners: the American Red Cross, the U.S. Centers for Disease Control and Prevention (CDC), the United Nations Foundation (UNF), the United Nations Children's Fund (UNICEF), and the World Health Organization (WHO). • 16. "Grants from various donors made to the UN Foundation specifically for the M&RI are pooled together with contributions from the UN Foundation. Initially, the UN Foundation matched donor funds and then moved to a straight contribution when donor contributions became too large to match. "A schedule of SIAs is projected over several years based on routine coverage and the quality and coverage of previous SIAs. Countries planning to conduct SIAs are requested to submit a Plan of Action (PoA), approved by each country’s Interagency Coordinating Committee (ICC), which includes target populations and budgets. The WHO and UNICEF develop an annual global budget for measles and rubella activities based upon these PoAs. "Each year, UNICEF and WHO submit one joint proposal to the UN Foundation for measles mortality reduction/elimination activities to be conducted in each of the six WHO regions. Based upon the budgets for these activities, the UN Foundation disburses funding to WHO and UNICEF according to the proposal request. Funds then flow from the UN Foundation to the UN Fund for International Partnerships (UNFIP) within the United Nations Secretary General’s office and then to the UNICEF and WHO headquarter offices. "UNICEF HQ disburses funds to country offices to cover operational activities and technical assistance and directly to the UNICEF SD for approved orders of bundled vaccines and devices. WHO HQ disburses funds to WHO Regional offices for disbursement to country offices, from which campaign activities are scheduled. UNICEF and WHO submit one joint progress report to the UN Foundation on a yearly basis, which is made available to all M&RI donors and partners." Measles and Rubella Initiative Annual Report 2014, p. 42. • 17. "M&RI estimates that$2.6 billion is required from 2015-2020 to further advance measles, rubella, and congenital rubella syndrome control activities in the 77 M&RI focus countries." Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015. Page 32 lists the 77 priority countries. Table 1 on p. 15 breaks down resource requirements for 2015-2020.

• 18.

"In response to a campaign funding gap, M&RI will first prioritize its vaccination activities over other activities, then consider reducing the campaign’s scale, and finally consider delaying the campaign. All of these responses have a negative impact on the campaign’s quality." GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016, p. 2.

• 19.
• "The estimates summarized in this document reflect requirements to support activities to be implemented by national governments with both internal and external support." Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p. 27.
• "Achieving immunization targets ultimately rests with national authorities. Nevertheless, partners play an essential role in providing technical assistance to national governments in planning and implementing programmatic activities." Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p. 24.
• "Countries planning to conduct SIAs are requested to submit a Plan of Action (PoA), approved by each country’s Interagency Coordinating Committee (ICC), which includes target populations and budgets. The WHO and UNICEF develop an annual global budget for measles and rubella activities based upon these PoAs.

"Each year, UNICEF and WHO submit one joint proposal to the UN Foundation for measles mortality reduction/elimination activities to be conducted in each of the six WHO regions. Based upon the budgets for these activities, the UN Foundation disburses funding to WHO and UNICEF according to the proposal request. Funds then flow from the UN Foundation to the UN Fund for International Partnerships (UNFIP) within the United Nations Secretary General’s office and then to the UNICEF and WHO headquarter offices.

"UNICEF HQ disburses funds to country offices to cover operational activities and technical assistance and directly to the UNICEF SD for approved orders of bundled vaccines and devices. WHO HQ disburses funds to WHO Regional offices for disbursement to country offices, from which campaign activities are scheduled. UNICEF and WHO submit one joint progress report to the UN Foundation on a yearly basis, which is made available to all M&RI donors and partners." Measles and Rubella Initiative Annual Report 2014, p. 42.
• 20.

"M&RI funds up to 50 percent of the operational costs for follow-up SIAs. M&RI requires that countries finance the other 50 percent of the operations costs. Countries are able to raise the balance from either government budget and/or in-country partner resources. For Gavi-supported SIAs, Gavi provides $0.65 per target individual - equaling 69 percent of operational costs – and government and other partners are expected to cover the balance." Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p. 18. • 21. "Under the new package, the Vaccine Alliance’s support for measles and rubella vaccination between 2016 and 2020 will rise from US$ 600 million to around US$820 million." Gavi December 2015 press release. • 22. • "Gavi restricts its measles campaign funding for measles follow-up vaccination campaigns to children under 5. Dr. Cochi explains that this is because Gavi currently has established a funding ceiling and prioritizes younger children as this age group has a higher likelihood of dying of measles." GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016, p. 2. • "The proposed measles and rubella strategy ... "(a) Extend the current measles SIA support from 6 large countries, to all the Gavi eligible countries that require measles SIA at national or subnational levels before introducing MR, focusing on children up to 5 years of age; "(b) Continue to provide 9 month-14 year old wide age initial MR catch-up campaigns for all Gavi eligible countries; "(c) Include follow up M or MR campaigns for all Gavi eligible countries, noting that the timing, scope and geographical distribution of follow-up campaigns will be driven by measles epidemiology." Gavi's measles and rubella strategy, report to the board, December 2015, p. 5-6 (section B, 5.5). These proposals were approved by the board of Gavi: See Decision 8, "Approved a comprehensive measles and rubella strategy for Gavi as set out in section B, 5.5-5.16 of Doc 10 to the PPC (the proposed "Measles and Rubella Strategy"), as amended by discussions at the PPC, and noting the additional funding for the current strategy period (2016-2020) amounts to approx. US$ 220 million." Gavi board decisions, December 2015, p. 19. We are not aware of the nature of any amendments.
• 23.

"Countries are eligible to apply for Gavi support when their Gross National Income (GNI) per capita is below or equal to US$1,580 on average over the past three years (according to World Bank data published every year on 1 July)." Gavi website: Countries eligible for support, which includes the 2016 list of eligible countries. • 24. Comparing the countries listed as M&RI priority countries (Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p. 32) with 2016 Gavi-eligible countries (Gavi website: Countries eligible for support), the 25 M&RI priority countries which are not eligible for Gavi support are: Algeria, Angola, Azerbaijan, Bolivia, Botswana, Cape Verde, Congo (Brazza), Dominican Republic, Equatorial Guinea, Gabon, Indonesia, Iraq, Kiribati, Lebanon, Micronesia, Namibia, Philippines, South Africa, Swaziland, Samoa, Syria, Timor Leste, Tuvalu, Vanuatu, Viet Nam. • 25. See GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016, p. 2 for an outline of activities not covered by Gavi funds: "The Gavi funds will not cover M&RI’s work in the following areas: 1. Campaigns for children aged 5 and up: Gavi restricts its measles campaign funding for measles follow-up vaccination campaigns to children under 5. Dr. Cochi explains that this is because Gavi currently has established a funding ceiling and prioritizes younger children as this age group has a higher likelihood of dying of measles. 2. Campaigns in countries not eligible for Gavi funding: Gavi funding is restricted to campaigns in 54 low and lower-middle income countries. M&RI supports vaccination activities in 77 countries, and its support system which includes surveillance and immunization policy development encompasses the entire world. 3. Many of M&RI’s support activities such as surveillance and coordination with Ministries of Health in 77 priority countries." • 26. • "In general, the currently used live, attenuated measles vaccines are effective in inducing protective immunity." WHO Module 7: Measles, 2009, p. 27. • "The highly effective, safe and relatively inexpensive measles- and rubella-containing vaccines protect individuals from infection, and their widespread use can completely stop the spread of the viruses in populations that achieve and maintain high levels of immunity. Countries began using measles vaccines in the 1960s, and immediately identified their use as highly cost-effective." WHO Global measles and rubella strategic plan, 2012-2020, p. 10. • Three cohort studies, summarized in a Cochrane review of efficacy and safety of vaccination for measles, mumps, and rubella, investigate the effectiveness of the measles vaccine component. • "Summary of main results: MMR vaccination would be highly effective (≥ 95%) in preventing clinical measles cases in preschool children and estimates were similar for each of the two measles strains with which participants had been immunised (Schwarz or Edmonston-Zagreb, one cohort study, n = 2745). The MMR vaccine (unspecified composition) is also about 98% effective in preventing laboratory-confirmed cases in children and adolescents (one cohort study, n = 184). Effectiveness in preventing secondary measles cases among household contacts was 92% for one and 95% for two vaccine doses (one cohort study, n = 175)." Demicheli et al. 2012, p. 19. • The success of widespread measles vaccination in controlling and eradicating the disease is good evidence that the vaccine is highly effective. • "As reported in the conclusions, vaccine efficacy is in any case out of the question, since we consider as important point of evidence the fact that in many countries eradication of the targeted diseases could be achieved by means of mass immunisation programs." Letter from the authors in response to feedback, Demicheli et al. 2012, p. 163. • Primary vaccine failure refers to a vaccine's failure to produce seroconversion. Secondary failure of a vaccine occurs when clinical measles occurs even after vaccine-induced seroconversion. A meta-analysis of studies of secondary failure of measles vaccine concluded that "Although reports of measles related to secondary failure exist, studies that permit the calculation of the rate of secondary failure demonstrate that the rate appears to be < 0.2%." Anders et al. 1996, abstract. • 27. • "The live attenuated measles vaccines currently used have a history of proven safety and effectiveness over the past 40 years, and have resulted in dramatic reductions in measles incidence, morbidity and mortality." WHO Module 7: Measles, 2009, p. 34. • Although a Cochrane review identified some increased risk of aseptic meningitis and febrile seizures from vaccine components prepared with certain strains of mumps, "Based on the identified studies, no significant association could be assessed between MMR immunisation and the following conditions: autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn’s disease, demyelinating diseases, bacterial or viral infections." Demicheli et al. 2012, p. 19. • 28. • "The measles/mumps/rubella (MMR) or measles/rubella (MR) vaccine is given in many countries instead of monovalent measles vaccine. The measles vaccines that are now internationally available are safe and effective and may be used interchangeably in immunization programmes." WHO Measles vaccine web page. • "Measles and rubella vaccine (MR) demand also increased due to countries introducing the vaccine with GAVI support. From 2011 to 2013, demand increased from 9 million to over 100 million." UNICEF MCV Supply Update 2013, p.1. • In 2015, the majority of UNICEF-procured measles-containing vaccines were measles monovalent vaccines. UNICEF procured 295.6 million doses of measles-containing vaccines (57% M, 38% MR, 5% MMR). UNICEF Vaccine Procurement (Volume). • 29. "Licensed combination vaccines do not reduce the immunogenicity of the measles vaccine component." WHO Module 7: Measles, 2009, p. 6. • 30. "Young infants in the first months of life are protected against measles by passively acquired maternal IgG antibodies. An active transport mechanism in the placenta is responsible for the transfer of IgG antibodies from the maternal circulation to the fetus, starting at approximately 28 weeks gestation and continuing until birth. Three factors determine the degree and duration of protection in the newborn: (1) the level of maternal antibodies to measles virus; (2) the efficiency of placental transfer; (3) the rate of catabolism in the child. Although protective, maternally-acquired antibodies also interfere with the immune responses to the attenuated measles vaccine by inhibiting replication of vaccine virus necessary for a robust immune response to the vaccine. In general, maternally-acquired antibodies are no longer present in the majority of children by six to nine months of age." WHO Module 7: Measles, 2009, p. 21. • 31. • This value is based on Cutts, Grabowsky, and Markowitz 1995, a review of 30 studies on the serological response to measles vaccine in infants aged less than 9 months. Although this review does not report an aggregated mean or median percent efficacy, we agree that the body of evidence presented there supports the use of 85% as an estimate of efficacy when the vaccine is administered at 9 months of age. • Uzicanin and Zimmerman 2011, a review of vaccine efficacy studies published in 1960-2010, found the following: "For a single dose of vaccine administered at 9–11 months of age and ≥12 months, the median VE [vaccine effectiveness] was 77.0% (interquartile range [IQR], 62%–91%) and 92.0% (IQR, 86%–96%), respectively. When analysis was restricted to include only point estimates for which vaccination history was verified and cases were laboratory confirmed, the median VE was 84.0% (IQR, 72.0%– 95.0%) and 92.5% (IQR, 84.8%–97.0%) when vaccine was received at 9–11 and ≥12 months, respectively. Published VE vary by World Health Organization region, with generally lower estimates in countries belonging to the African and SouthEast Asian Regions." p. S133. • 32. • "Based on the available evidence, one MMR vaccine dose is at least 95% effective in preventing clinical measles," Demicheli et al. 2012, p. 1 (Main results). Although this conclusion is based only on three cohort studies, we consider the long history of use of measles vaccines and the success of mass vaccination in eliminating measles in some countries in accepting this widely-cited estimate of vaccine efficacy. • Sudfeld, Navar, and Halsey 2010, p. 1 • "We identified three measles vaccine RCTs [randomized controlled trials] and two QE [quasi-experimental] studies with data on prevention of measles disease. A meta-analysis of these studies found that vaccination was 85% [95% confidence interval (CI) 83–87] effective in preventing measles disease." • "The literature also suggests that a conservative 95% effect estimate is reasonable to employ when vaccinating at 1 year or later." • The studies included children under 12 months of age, when lower levels of vaccine efficacy are expected. • "For a single dose of vaccine administered at 9–11 months of age and ≥12 months, the median VE [vaccine effectiveness] was 77.0% (interquartile range [IQR], 62%–91%) and 92.0% (IQR, 86%–96%), respectively. When analysis was restricted to include only point estimates for which vaccination history was verified and cases were laboratory confirmed, the median VE was 84.0% (IQR, 72.0%– 95.0%) and 92.5% (IQR, 84.8%–97.0%) when vaccine was received at 9–11 and ≥12 months, respectively. Published VE vary by World Health Organization region, with generally lower estimates in countries belonging to the African and SouthEast Asian Regions." Uzicanin and Zimmerman 2011, p. S133. • 33. "The proportion of children who develop protective antibody levels following measles vaccination depends on the presence of inhibitory maternal antibodies and the immunologic maturity of the vaccine recipient, as well as the dose and strain of vaccine virus." WHO Module 7: Measles, 2009, p. 10. • 34. "Among older children, who have no passive protection from maternal antibody, measles vaccines are highly efficacious and seroresponse does not vary according to virus strain or the titer of the vaccine (for titers higher than 3.0 log10 infectious units per dose)." Cutts, Grabowsky, and Markowitz 1995, p. 95. • 35. "Several studies have demonstrated that higher effectiveness occurs in children vaccinated at 15 months compared with those vaccinated at 12 months, but that the protection conferred does not seem to improve further if the first dose is given at beyond 15 months of age." WHO Weekly Epidemiological Record 2 April 2004, p. 137. • 36. "The duration of immunity following measles vaccination is more variable and shorter than following wild-type measles virus infection, but persists for decades. Even in countries where measles is no longer endemic, antibodies to measles virus persist for years (Table 6, Figure 5). In countries where measles remains endemic, or in early studies where measles vaccine coverage rates were low, immune responses may be boosted by re-exposure to wild-type measles virus. The antibody levels induced by vaccination decline over time and may become undetectable. Nevertheless, immunological memory persists and, following exposure to measles virus, most vaccinated persons produce a measles virus-specific immune response without clinical symptoms." WHO Module 7: Measles, 2009, p. 28. See also citations 26, 106-108 to studies of duration of immunity. We have not examined these studies. • 37. • "The World Health Organization recommends a minimum potency for measles vaccine of 1000 viral infective units (3.0 log10 TCID50)." WHO Module 7: Measles, 2009, p. 5. • "Measles vaccines are relatively heat-stable in the lyophilized form, but rapidly lose potency when exposed to heat after reconstitution. The development of effective stabilizers and the formulation of the World Health Organization requirement for heat stability for freeze-dried measles vaccine considerably improved the quality of measles vaccines. In the freeze-dried state, measles vaccines that meet World Health Organization requirements retain a minimum potency of at least 3.0 log10 live virus particles per human dose after exposure to a temperature of 37°C for at least one week. However, reconstituted measles vaccines may lose their potency at room temperatures. Although the stability depends in part upon the particular vaccine strain, reconstituted measles vaccines may lose approximately 50% of potency in one hour at 22°C to 25°C, and are inactivated within one hour at temperatures over 37°C." WHO Module 7: Measles, 2009, p. 5. • Studies of vaccine efficacy in Nigeria have observed high rates of vaccine impotency and associated lower rates of vaccine efficacy: "Forty-three received potent vaccines of which 35 returned for the post-vaccination with seroconversion in 26. Non-potent vaccines were administered to 51 of which 42 returned for the post-vaccination sampling with seroconversion in 18. The seroconversion rates in the two groups were thus 74.3% and 42.9% respectively." Ladapo et al. 2013, p. 256. • 38. We have little visibility into the quality of vaccine cold chain during SIAs. We have found no studies of cold chain, vaccine potency loss, or seroconversion during and after SIAs. "Comparisons between HIV-infected and HIV-exposed but uninfected children showed lower levels of seropositivity in HIV-infected children at 12 months (RR [relative risk], 0.61; 95% CI [confidence interval], .50–.73)." Scott et al. 2011 p. S171, a review of 39 studies published 1987-2008. We have not closely examined the effect of HIV infection on measles vaccination or on measles infection. • 39. "In most developing countries, children are vaccinated against measles at 9 months of age, when seroconversion rates of 80–85% may be expected." WHO Weekly Epidemiological Record 2 April 2004, p. 137. • 40. "During 2000–2015, the number of countries providing MCV2 nationally through routine immunization services increased from 97 (51%) to 160 (82%), with six countries (Angola, Malawi, Mozambique, Nepal, Sierra Leone, and Zimbabwe) introducing MCV2 in 2015." CDC, Progress Toward Regional Measles Elimination — Worldwide, 2000–2015. • 41. See the MCV2 coverage in WHO Measles reported MCV1, MCV2 coverage by country (1980-2016) (HTML) for countries listed in WHO Summary of Measles SIAs 2000 to 2017 (Excel 290kb). • 42. Summary of data sources for routine immunization coverage: WHO Data and statistics web page. • 43. WHO/UNICEF Estimates of National Immunization Coverage by country (1980-2015) (HTML) • 44. • "Coverage estimates based on administrative data are mainly subject to numerator (children vaccinated) and denominator (target population) biases. When too small a numerator is used because vaccinations are not reported by lower administrative levels or part of the population, such as the private sector, is excluded from the data collection or reporting system, coverage can be underestimated. It can also be overestimated when children vaccinated outside the target age group are erroneously included in the numerator. Estimates based on administrative data can also be biased by an inaccurate denominator, especially when outdated censuses and poor population projections are used. For instance, when coverage is high and the target population has been underestimated, estimated coverage can exceed 100%. "Survey data allow for estimating immunization coverage even if the size of the target population is unknown; they also include vaccinations given by the private sector. Their main disadvantage, however, is their lack of usefulness for timely programme interventions because they provide information only on the previous birth cohorts. In addition, they may yield confidence intervals that are wider than desired, interviewers may be poorly trained, supervision may be weak and analyses may be erroneous. Because surveys are rarely performed at the district level or lower, they do not provide information on local system performance. Respondent recall biases may be significant and their direction may be unknown. In some instances, the length or complexity of the questionnaire may compromise the accuracy of the responses. Finally, as with any survey, the results may be inappropriately generalized beyond the survey population. "Both administrative and survey methods are vulnerable to inadvertent recording, calculation and transcription errors; non-compliance with the established protocol due to poor training and supervision, and systematic and purposeful data fabrication." • "One perceived weakness of the estimates stems from the subjective nature of the methods used. As described above, the heuristics used constrain but do not uniquely determine the estimate." • "Current estimates are seriously limited by the absence of any articulation of uncertainty; as presented, they appear equally precise and certain. The uncertainty in the estimates is rooted in the accuracy and precision of the empirical data (described above) and in the choice and application of the heuristics (model-based uncertainty)." • "Finally, the quality of the estimates is determined by the quality and availability of empirical data." • 45. • "In July 2002, after the measles catch-up SIA, a national household coverage survey was conducted by the Kenya Ministry of Health to assess vaccination coverage. Measles vaccine coverage was evaluated in the target population, children aged 9 months through 14 years, as well as the immunization status for all antigens for children aged 9–23 months. The design and methods of this survey are described in detail in the Kenyan evaluation report [10]. Using a cluster survey design, a total of 7637 households were surveyed covering 18,922 children aged 9 months to 14 years, yielding a sufficient sample size to estimate provincial-level routine and SIA vaccine coverage." Vijayaraghavan et al. 2007, p. 29. • "Nationwide, more than three-quarters (77%; 95% CI [confidence interval]: 75%, 80%) of children aged 9–23 months received the measles vaccine through routine health services before the SIA (Fig. 2). The nationwide coverage of the 2002 SIA in these children was 90% (95% CI: 88%, 91%), a statistically significant increase over routine coverage. Among children aged 9–23 months, compared to the routine measles vaccine coverage, the SIA resulted in statistically significant increases in coverage in five provinces: [...] In Nairobi, Central and Coast Provinces, the measles vaccine coverage achieved through the SIA was not statistically different from that achieved through routine health services." Vijayaraghavan et al. 2007, p. 30. • "Nationwide measles vaccine coverage among the poorest, second and fourth wealth quintiles increased significantly as a result of the SIA (Fig. 3): coverage in the poorest wealth quintile increased from 65% (95% CI: 59%, 70%) routine coverage to 86% (95% CI: 82%, 90%) as a result of the SIA, from 71% (95% CI: 66%, 77%) to 92% (95% CI: 88%, 95%) in the second poorest quintile, and from 80% (95% CI: 75%, 84%) to 92% (95% CI: 89%, 95%) in the fourth poorest quintile. In the middle and richest wealth quintiles, the measles vaccine coverage was similar for routine and SIA." Vijayaraghavan et al. 2007, p. 30. • "In all five provinces with routine coverage less than 80%, coverage with the SIA was higher than that achieved through routine health services, while Nairobi, Central and Coast Provinces with routine coverage greater than 80% did not see a statistically significant change in coverage as a result of the SIA. These results highlight the difficulty of reaching the small percentage of previously unreached sections of the population in high-coverage provinces." Vijayaraghavan et al. 2007, p. 33. • "Children born in families belonging to the two poorest wealth quintiles were the biggest beneficiaries of the SIA, with significant increases in measles vaccine coverage compared to the routine vaccination program." Vijayaraghavan et al. 2007, p. 34. • 46. • "We conducted a cluster survey in two cities within the areas covered by the measles vaccine campaign. Altogether, 121 clusters of 7 children were randomly selected in Ouagadougou (four health districts) and 60 clusters were selected in Bobo Dioulasso (two health districts) using a two-stage sampling method. The 30 sectors of Ouagadougou and the 25 sectors of Bobo Dioulasso were used as secondary stratification levels." Zuber et al. 2001, p. 297. • "Altogether, 604 (57%; 95% confidence interval (CI)=54– 61%) of children aged 9–59 months had had a measles vaccination documented before the campaign. Of the children surveyed, 823 (79%; 95% CI = 76–83%) received measles vaccine during the immunization days. In total, 943 of the 1041 children (91%;95%CI=88–93%) had received measles vaccine at least once either routinely or through the campaign." Zuber et al. 2001, p. 298. (943 - 604) / (1041 - 604) = approximately 78% of children who had not been vaccinated before the campaign were vaccinated during the campaign. • "Children whose principal caregiver had had no education were less likely than others to have been routinely vaccinated against measles prior to the campaign (49% in contrast to 68%; relative risk (RR) 0.71, 95% CI [confidence interval] = 0.63–0.81). Routine coverage increased as the level of the caregiver’s education increased (Table 2)." Zuber et al. 2001, p. 298. • "Predictors of a missed routine vaccination were not associated with better coverage during the NIDs [National Immunization Days, the SIA this study evaluates]. In particular, children whose principal caregiver had had no education were as likely to be vaccinated during the immunization days as other children were (79% vs. 80%; RR 0.99, 95%CI=0.91–1.07) (Table2)." Zuber et al. 2001, p. 298. • "The coverage estimates found in the survey were substantially different from those obtained from information on the number of doses administered (Table 4). For the six districts combined, the administrative information suggested that coverage was 107%, while coverage measured by the survey was 79% (95% CI = 76–83%). Thus, the administrative method overestimated actual coverage by 35%. In addition, the district with the highest administrative coverage (Bobo Dioulasso sector 22) was also that with the lowest coverage as measured by the survey." Zuber et al. 2001, p. 298. • 47. "The MR Initiative will support research activities that provide evidence-based strategies to address the challenges posed by high levels of population movement within and between countries, which exist in South Asia and West Africa. In addition, it will focus efforts on developing the communication tools and strategies required to reach migrants and isolated populations, including religious groups that typically do not interact with national health systems." WHO Global measles and rubella strategic plan, 2012-2020, p. 31. • 48. Summary of data sources for administratively reported SIA coverage: • 49. • 50. "During 2011–2012, approximately 133 million children were vaccinated during 35 measles SIAs (Table 2). Of these SIAs, 23 (66%) had >95% national level administrative coverage and of the 27 with available information, 4 (15%) had >95% MCV administrative coverage in all districts. Among the 20 SIAs for which there was a post-SIA coverage survey, 19 (95%) had lower coverage estimated by survey than by administrative report (Table 2)." WHO Progress towards measles pre-elimination, African Region, 2011–2012, p. 142. • 51. "Coverage estimates based on administrative data are mainly subject to numerator (children vaccinated) and denominator (target population) biases. When too small a numerator is used because vaccinations are not reported by lower administrative levels or part of the population, such as the private sector, is excluded from the data collection or reporting system, coverage can be underestimated. It can also be overestimated when children vaccinated outside the target age group are erroneously included in the numerator. Estimates based on administrative data can also be biased by an inaccurate denominator, especially when outdated censuses and poor population projections are used. For instance, when coverage is high and the target population has been underestimated, estimated coverage can exceed 100%." WHO/UNICEF Estimates of National Immunization Coverage (Methods). • 52. • 53. "Four types of surveys are commonly used to estimate vaccination coverage in developing countries: demographic and health surveys, multiple indicator cluster surveys, Expanded Programme on Immunization cluster surveys and surveys based on lot quality assurance sampling." Kaiser et al. 2015, p. 314. • 54. • 55. "During 2011–2012, approximately 133 million children were vaccinated during 35 measles SIAs (Table 2). [...] Among the 20 SIAs for which there was a post-SIA coverage survey, 19 (95%) had lower coverage estimated by survey than by administrative report (Table 2)." WHO Progress towards measles pre-elimination, African Region, 2011–2012, p. 142. • 56. • 57. • "Methods We reviewed surveys that were conducted to evaluate supplementary measles immunization activities in eastern and southern Africa during 2012 and 2013. We investigated the organization(s) undertaking each survey, survey design, sample size, the numbers of study clusters and children per study cluster, recording of immunizations and methods of analysis. We documented sampling methods at the level of clusters, households and individual children. We also assessed the length of training for field teams at national and regional levels, the composition of teams and the supervision provided." Kaiser et al. 2015, p. 314. • "Findings The surveys were conducted in Comoros, Eritrea, Ethiopia, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, Swaziland, Uganda, Zambia and Zimbabwe. Of the 13 reports we reviewed, there were weaknesses in 10 of them for ethical clearance, 9 for sample size calculation, 6 for sampling methods, 12 for training structures, 13 for supervision structures and 11 for data analysis." Kaiser et al. 2015, p. 314. • The discussion of methodological concerns is too lengthy to reproduce here. Shortcomings of the survey reports include: lack of information on sampling size and methods, lack of interviewer training, unclear randomization methods, vaccination evaluation using finger marks long after finger marks are expected to fade, not reporting survey dates, unclear analytic methods. See especially Kaiser et al. 2015 p. 315. • Survey leadership: "According to unpublished documents submitted to WHO, five (38%) of the 13 surveys were led by a local consultant or consultant firm, one (8%) by a national research institute – with technical support from consultants from several international organizations, four (31%) by WHO’s office in Harare, Zimbabwe, and two (15%) by international WHO consultants." Kaiser et al. 2015, p. 315. • Coverage survey results: "In nine (69%) of the 13 surveys reported, the supplementary immunization-coverage estimate based on the survey results was lower than that based on the corresponding, routinely collected administrative data. Based on finger marks, immunization cards or the recall of members of the study households, the survey results indicated a median coverage of 93% (range: 81–98%). However, the corresponding value based only on finger marks or cards was only 62% (range: 3–91%)." Kaiser et al. 2015, p. 315. • 58. • Vijayaraghavan et al. 2007, p. 29. • "In July 2002, after the [June 2002] measles catch-up SIA, a national household coverage survey was conducted by the Kenya Ministry of Health to assess vaccination coverage." • "Using a cluster survey design, a total of 7637 households were surveyed covering 18,922 children aged 9 months to 14 years, yielding a sufficient sample size to estimate provincial-level routine and SIA vaccine coverage." • "Routine and SIA measles vaccination was assessed by reviewing child health cards on which routine immunizations were recorded, and the cards that were distributed in the SIAs as proof of vaccination, as well as respondents’ recall of both routine and SIA vaccination. In this paper, we restricted our analysis to the sample of 1455 children aged 9–23 months, to enable comparison of measles vaccine coverage through pre-SIA routine health services with coverage attained through the SIA." • "The design and methods of this survey are described in detail in the Kenyan evaluation report." We have been unable to find this report describing the survey methodology. • "Among children aged 9–23 months included in the household survey, 59% had child health cards, 83% had cards distributed during the SIA for proof of vaccination and 53% were male. Nationally, 75% of children aged 12–23 months were fully vaccinated; however, there were great differences by province." Vijayaraghavan et al. 2007, p. 30. • 59. "Of an estimated 1,748,829 eligible children in the target districts, 1,339,236 (77%) were vaccinated (table 1). Of the five central region provinces, two reported coverage of >90% and two >80%. Coverage was lowest in Kabul city (62%). However, since many families fled Kabul with the Taliban, the 2001 NIDs [national immunization days] population may have overestimated the remaining target population. "Despite extending the duration of the campaign in Kabul by 7 days and sending external monitors to search door-to-door for missed children, reported coverage was still low. Thus, a population-based survey was conducted. Results showed that of 890 households with 3537 children aged 6 months to 12 years, 91% (95% confidence interval [CI], 0.85–0.91) of children aged 6 months to 5 years and 88% (95% CI, 0.87–0.95) of children aged 5–12 years were vaccinated during the campaign. An ACF [Action Contre la Faim] survey in the Panjshir Valley that included four districts in Kapisa and two in Parwan provinces found 85% measles vaccine coverage among children aged 9–59 months." Dadgar et al. 2003, p. S189. This paper does not describe the survey methodology and does not cite further source documentation for the survey. • 60. • "Methods: During the week after the campaign, in which measles vaccine was offered to children aged 9–59 months in six cities regardless of vaccination history, a cluster survey was conducted in Ouagadougou and Bobo Dioulasso, the country’s two largest cities. Interviewers visited the parents of 1267 children aged up to 59 months and examined vaccination cards. We analysed the data using cluster sample methodology for the 1041 children who were aged 9–59 months." Zuber et al. 2001, p. 296. Survey methodology is further discussed on p. 297: "The survey took place during the week immediately following the vaccination campaign. Data were collected using closed questions. Interviews were conducted with the principal caregiver of every child. If the caregiver was absent, interviewers registered the name of the child and returned to complete data collection." • "Findings: A total of 604 (57%) children had received routine measles vaccination prior to the campaign, and 823 (79%) were vaccinated during the NIDs [national immunization days]. Among those who had previously had a routine vaccination, 484 (81%) were revaccinated during the NIDs. Among those not previously vaccinated, 339 (78%) received one dose during the NIDs. After the campaign, 943 (91%) children had received at least one dose of measles vaccine. Better socioeconomic status was associated with a higher chance of having been vaccinated routinely, but it was not associated with NID coverage." Zuber et al. 2001, p. 296. • 61. In many countries, initiating regular SIA campaigns coincides with increasing routine MCV1 coverage, making it difficult to understand which effects to attribute to which intervention. We have observed a few historical cases in which either countries without SIAs significantly increased routine MCV1 coverage, or SIAs were conducted during a period of little change in routine immunization coverage. These examples show that each intervention can be effective without the other. • In three African countries whose routine immunization coverage increased from roughly 50% to roughly 80% in the 1990s (prior to SIA campaigns), reported measles cases decreased by around 50%. Otten et al. 2003, p. S39. • "Figure 1 shows trends in measles cases and routine measles immunization coverage from 1981 to 2000 for Ghana, Cote D’Ivoire, and Mozambique. On average, there was about a 50% decline (range, 41%–53%) in reported measles cases when routine immunization increased from 50% in the early or mid-1990s to 73%–90% in 1999." • "In Ghana, a mean of 33,513 measles cases occurred during 1991–1996, when routine coverage was 40%–53%, and 19,687 (a decline of 41%) during 1997–2000, when routine coverage increased from 59% in 1997 to 84% in 2000." • "In Cote d’Ivoire, a mean of 16,606 measles cases occurred during 1991–1996, when routine coverage was 41%–56%, but just 7859 (a decline of 53%) during 1997–2000, when routine coverage was 57%–73%." • "In Mozambique, a mean of 15,093 measles cases was reported for 1981–1990, when routine measles vaccine coverage was 32%–59%, and 7931 cases during 1991–2000 (a decline of 47%), when routine coverage increased from 55% in 1991 to 87%–97% in 1998–2000." • "In Ghana, Mozambique, and Cote d’Ivoire, it took 4–9 years for routine immunization coverage to increase from about 50% to ≥80%. Although reported cases declined over time in all three countries, in 2000 cases rebounded to >15000 in Mozambique and Cote d’Ivoire and >123,000 in Ghana." • In Ethiopia, a large national catch-up campaign was conducted (67% of the country in 2003, 33% in 2004) during a period of very steady MCV1 coverage (35-37% in 1999-2004), resulting in a 93% decline from an average of about 3,170 cases per year (1999-2002) to an average of about 220 cases per year (2003-2005). WHO Summary of Measles SIAs 2000 to 2017 (Excel 290kb), WHO/UNICEF Estimates of National Immunization Coverage by country (1980-2015) (HTML), and WHO Measles reported cases by country (1980-2016) (HTML). • 62. "Catch-up campaigns were conducted throughout Central America in 1992 and 1993, reaching 89% of children. In South America, Brazil, Chile, and Peru catch-up campaigns were performed in 1992. In 1993, similar catch-up campaigns were completed in Argentina, Colombia, the Dominican Republic, and Mexico. As a result, reported measles cases in the region reached a historic low in 1993 (n=57,400), a rate of 10 measles cases per 100,000 population." Castillo-Solorzano et al. 2011, p. S271. Although it is difficult to separate the effect of rising routine coverage (black line), mass immunization campaigns (vertical arrows) appear to effect sharp drops in measles cases (red bars) from >250,000 in 1980 to zero in 2003. The graphic is from Castillo-Solorzano et al. 2011, p. S275. This graphic from Bishai et al. 2010, p. 117 illustrates a sharp and lasting decline in cases coinciding with SIA campaigns in Colombia. In the case of Brazil, the trend is less striking due to a large resurgence of measles cases and incomplete data. Bishai et al. 2010, p. 103: • 63. • "In 1996, the seven southern African countries agreed on a plan to eliminate measles. The strategy consisted of routine immunization for babies at 9 months, a nationwide catch-up campaign to provide a second opportunity for immunization to all children aged 9 months to 14 years, and follow-up campaigns in young children every three to four years. In addition, the countries organized surveillance for cases of measles and improved laboratory facilities so that suspect cases could be confirmed." WHO Module 7: Measles, 2009, p. 1. • "By 2000, six of the seven countries (all but Lesotho) had completed their catch-up campaigns. For these six, surveillance data could therefore be analyzed. In 1996, they had reported a total of 60,000 measles cases; by 2000, the number of confirmed cases was just 117, a reduction of close to 100 percent. The number of reported measles deaths had been 166 in 1996; in 2000, it was zero." WHO Module 7: Measles, 2009, p. 5. • "However, in 2002 and 2003 more serious outbreaks occurred. Cases believed to have been imported across the border from neighboring Angola triggered one outbreak in Engela in northern Namibia and, it is thought, another outbreak in the capital, Windhoek. The outbreak in Namibia continued for 18 months between 2002 and 2003, resulting in 1,218 reported cases and 13 deaths. Transmission was subsequently interrupted following a major vaccination campaign in June 2003. In Zimbabwe an outbreak started in September 2003, primarily among children whose parents refused vaccination on religious grounds, causing 80 cases and 20 reported deaths. Another outbreak was detected in Johannesburg and was traced to an immigrant community." WHO Module 7: Measles, 2009, p. 7. • 64. • "Between 2000 and June, 2003, 82.1 million children were targeted for vaccination during initial SIA in 12 countries and follow-up SIA in seven countries. The average decline in the number of reported measles cases was 91%." Otten et al. 2005, p. 832. • "In the 12 western and eastern African countries, the number of reported measles cases declined from 85 000–250 000 during 1990–2001 to 12 073 in 2003 (figure). In the seven southern African countries, the number of reported measles cases fell from 24 000–140 000 during 1990–97 to 2081–7057 per year from 1999 to 2003 (figure). The average proportional decrease in reported measles cases was 89% for the 12 eastern and western African countries and 91% for all 19 countries (table 2). Three countries had an average decline of less than 70%. The low percentage decreases for Burkina Faso (67%) and Namibia (65%) were probably due to measles outbreaks. The low percentage decrease for Botswana (64%) was probably due to misreporting of rubella cases as measles cases in 2000." Otten et al. 2005, p. 835. • The effect of a catch-up SIA is particularly pronounced in Uganda, as illustrated in Bishai et al. 2010, p. 167: • 65. Reported cases averaged about 3,170 cases per year in 1999-2002, and about 220 cases per year in 2003-2005. WHO Summary of Measles SIAs 2000 to 2017 (Excel 290kb) and WHO Measles reported cases by country (1980-2016) (HTML). • 66. See, for example, the case studies of Bangladesh and Tajikistan in Bishai et al. 2010. In Bangladesh (p. 88), an SIA campaign coincided with a large increase in cases, and was followed by a return to lower pre-outbreak levels. In Tajikistan (p. 152), measles cases appear to trend downward for many years before the SIA. The introduction of a second dose of vaccine (MCV2) delivered through routine health services may complicate the attribution of effect. • 67. "Despite high reported coverage for routine and supplementary immunization, in 2010 in Malawi, a large measles outbreak occurred that comprised 134,000 cases and 304 deaths. Although the highest attack rates were for young children (2.3%, 7.6%, and 4.5% for children <6, 6-8, and 9-11 months, respectively), persons >15 years of age were highly affected (1.0% and 0.4% for persons 15-19 and >19 years, respectively; 28% of all cases). A survey in 8 districts showed routine coverage of 95.0% for children 12-23 months; 57.9% for children 9-11 months; and 60.7% for children covered during the last supplementary immunization activities in 2008. Vaccine effectiveness was 83.9% for 1 dose and 90.5% for 2 doses. A continuous accumulation of susceptible persons during the past decade probably accounts for this outbreak." Minetti et al. 2013, p. 202. • 68. • "Methods: We retrospectively looked at the records of cases of measles in children admitted to the Wesley Guild Hospital, Ilesa over a ten year period (2001 - 2010); five years before and five years after the nationwide commencement of supplemental measles immunisation activities (SIAs) in the region in 2006. Measles cases were defined using the WHO case definition." Peter, Ademola, and Oyeku 2014, p. 131. • "We looked at the record of cases of measles admitted between year 2001 and 2010 by retrieving the files of all cases of complicated measles admitted during the period. All admitted children less than 15 years during the study period was also noted. The cases of measles were diagnosed clinically based on the WHO case definition criteria," Peter, Ademola, and Oyeku 2014, p. 132. • The SIA schedule consisted of a two-phase national catch-up reaching about 59 million children, and follow-up SIAs for children 9-59 months of age every 2 years. Peter, Ademola, and Oyeku 2014, p. 132. • "Results: Over the ten year study period, a total of 12,139 children were admitted and managed; out of which 302 (2.5%) were cases of complicated measles. There was no difference in the mean (SD [standard deviation]) of children admitted in the years before and after the introduction of the SIAs {6040 (122.7) vs.6099 (120.2); t-test 0.02, p =0.988.} There was however a remarkable reduction in the proportion of the cases of measles admitted after the introduction of SIAs compared to the period before SIAs (4.3% vs. 0.6% x2=169.580; p < 0.001)" Peter, Ademola, and Oyeku 2014, p. 131. • Table II on p. 133 of Peter, Ademola, and Oyeku 2014 shows 262 hospitalized measles cases and 5778 non-measles hospitalizations in 2001-2005 (4.3%), and 40 hospitalized measles cases and 6059 non-measles hospitalizations in 2006-2010 (0.66%). (262 - 40) / 5 = an estimated 44.4 complicated measles cases averted per year. • The study authors attribute the reduction in measles hospitalization to SIA vaccinations, but we are not confident in their analysis of attribution: "Routine immunization coverage rate in Nigeria and at the study location is low with measles immunization coverage ranging from 12.7% to 41.0% of children 12- 23 months during the study period. Since no significant change in the routine immunization coverage rate and the total number of children admitted before and after the introduction of the supplementation measles immunization campaign as well as other childhood health interventions during the period, the remarkable reduction in the number of admitted measles cases observed in this study following SIAs can only be due to the supplemental measles immunization campaigns." Peter, Ademola, and Oyeku 2014, p. 134. • 69. • "Beginning in 1999, Vietnam began conducting a series of subnational supplementary immunization activities (SIAs) in selected provinces. A national SIA targeting children aged 9 months to 10 years was conducted in the North Region in 2002 and in the South, Central, and Highland Regions in 2003. Older age groups (12–15 and 12–18 years) were targeted in selected districts of 20 provinces during 2004. In 2007, measles SIAs again were conducted in 17 of 29 provinces in the North Region, targeting persons 6–20 years of age; 4 of these (Lao Cai, Lai Chau, Dien Bien, and Ha Giang) also targeted children aged 9 months–5 years (Figure 2). In 2008, SIAs targeting persons 7–20 years of age were conducted in all 4 provinces in the Highland Region and in part of 1 province (Quang Nam) in the Central Region. Reported coverage in almost all provinces conducting SIAs since 2002 was ≥95%." Sniadack et al. 2011, p. S476. • "A total of 158 cases were reported from Vietnam during the last quarter of 2008. Measles transmission increased dramatically during early 2009 to involve ~8000 reported confirmed cases from 60 provinces as of January 2010." Sniadack et al. 2011, p. S477. • "Two sources of surveillance data were used to identify and classify suspected measles cases: measles case investigation forms (CIFs) submitted to the National Institute of Hygiene and Epidemiology (NIHE) EPI Unit and monthly line listing forms submitted by the 4 regional measles laboratories. Because laboratory data submissions reported more IgM-positive cases than did CIFs submitted to the NIHE EPI Unit, we added epidemiologically linked and clinically confirmed cases from CIF submissions to the IgM-positive cases reported in laboratory reports to determine numbers of cases by time, place, and age." Sniadack et al. 2011, p. S478. • "Protection From Supplementary Immunization Activities During 2007–2008. Among the 22 provinces that conducted SIAs during 2007–2008, 5 that had targeted all districts in the province reported an unexpectedly high incidence of confirmed measles during the epidemic period, ranging from 63 to 549 cases per million population. Incidence ranged from 45 to 129 cases per million when restricting analysis to laboratory-confirmed cases only. Two of the 5 provinces had targeted persons 9 months to 20 years of age during the 2007 SIAs; in these provinces, 126 (54%) of 233 confirmed cases were aged 3–22 years who should have been protected; 57 (24%) were aged <3 years, and 50 (21%) were aged ≥23 years. The remaining 3 provinces targeted persons either 6 or 7 to 20 years of age during their SIAs in 2007 or 2008, respectively; in these provinces, 188 (34%) of 549 cases were 8–22 years of age and should have been protected; 199 (36%) were <8 years of age, and 162 (30%) were ≥23 years of age." Sniadack et al. 2011, p. S480. • "The epidemic’s magnitude and geographic extent have been substantial, and the epidemiologic findings suggest both success and limitations of past elimination efforts. The rolling 2002–2003 catch-up SIA that targeted children aged 9 months to 10 years was successful in largely interrupting measles virus transmission and continued to protect persons who were 7–17 years of age during the 2009 epidemic. Incidence among children 5–9 and 10–14 years of age was very low, compared with other age groups and compared with reported measles cases before the 2002–2003 catch-up SIAs. However, the follow-up strategy of outbreak response immunization and subnational SIAs implemented during 2005–2008 and limited to provinces thought to be at risk for measles apparently left large numbers of susceptible children who acquired measles infection during this epidemic." Sniadack et al. 2011, p. S481. • 70. • "The Provincial Departments of Health in Mpumalanga and Western Cape identified the acute care hospitals in which patients with measles could have been cared for during 1992–1998. A questionnaire was sent by fax to these hospitals to request their participation in the study and to obtain baseline information about the availability of hospital records for the study period, annual number of measles hospitalizations, and hospital policy on admitting suspected measles cases. Hospitals that had a policy not to admit suspected measles cases and those without hospital registers available for review were excluded from the study." Uzicanin et al. 2002, p. 970. • "We could not assess the accuracy of the clinical diagnosis of measles in either the surveillance reports or in the hospital study because diagnoses were not routinely confirmed by serology before October 1998. Also, in the hospital study it was not possible to assess the appropriateness of other recorded diagnoses and the accuracy of the recorded hospitalization outcome." Uzicanin et al. 2002, p. 970. • "Sixteen of 27 public hospitals in Mpumalanga participated in the hospital study, representing 3512 (82%) acute-care hospital beds. One of six private hospitals participated. From January 1992 through April 1999, 1707 measles-related hospitalizations occurred in the participating hospitals (Figure 2). The average annual number of measles-related hospitalizations declined by 91%, from 329 during the 5 pre-campaign years to 29 in the first 2 post-campaign years (Table 3)." Uzicanin et al. 2002, p. 970-971. • "All 11 measles-associated deaths occurred among patients hospitalized during the pre-campaign period (1992–1996), for a pre-campaign case fatality ratio of 0.7 deaths per 100 measles-related hospitalizations." Uzicanin et al. 2002, p. 971. • "Twenty-seven of 34 acute-care public hospitals in Western Cape participated in the hospital study, representing 6300 (94%) acute care hospital beds in the public sector. Eight of 33 private hospitals participated. From January 1992 through July 1999, 765 measles-related hospitalizations occurred in the participating hospitals (Figure 3). Following the campaigns, the average annual number of measles-related hospitalizations declined by 84%, from 123 during the 6 pre-campaign years to 20 in 1998, the first post-campaign year (Table 5)." Uzicanin et al. 2002, p. 972 • "All 23 measles-related deaths occurred among patients hospitalized in 1992–1996 yielding a case fatality ratio of 3.1 deaths per 100 measles hospitalizations." Uzicanin et al. 2002, p. 974. • "Mpumalanga is a predominantly rural province in the northeast of South Africa. [...] Western Cape Province is urbanized with good infrastructure." Uzicanin et al. 2002, p. 969. • The study authors discuss the many limitations of this study, including entirely clinical diagnosis (no laboratory-confirmed surveillance), incompleteness of hospital records, coincidence of SIA campaigns with a measles epidemic, and short post-campaign observation time window. Uzicanin et al. 2002, p. 974. • This study also examined routine measles surveillance data reported on the national level. • 71. Gandhi and Lydon 2014, a review of operational costs incurred in-country, note that "The information documented in both existing literature and possibly the data from cMYPs [comprehensive Multi-Year Plans] may not be reflective of the full costs of implementing an SIA. In addition to the operational costs incurred mainly by national payers and reported in the literature and cMYPs, implementation of SIAs that are part of global ADC/E/E [accelerated disease control, elimination, and eradication] efforts often rely on additional expertise from global agents such as WHO, UNICEF, and the United States Center for Disease Control and Prevention (US CDC). [...] The costs associated with these additional support activities are often referred to as 'core costs' in agency budgets but are rarely factored into estimates of operational cost estimates to illustrate the true nature of SIAs." p. 12. • 72. We have inflation-adjusted reported costs using a US Inflation Calculator. In some cases, noted where appropriate, we guessed (e.g. based on publication date) as to the original year of reported costs. • 73. • 74. UNICEF Vaccine Price Data (Measles), adjusted to 2015 USD. • 75. UNICEF Vaccine Price Data (MR), adjusted to 2015 USD. • 76. UNICEF Vaccine Price Data (MMR), adjusted to 2015 USD. • 77. • 78. • 79. Budget assumptions for Gavi-eligible countries, Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p. 6: • "M&RI or GAVI wholly support bundled MCV costs." • "GAVI wholly supports bundled MCV costs for priority countries: Afghanistan, Chad, DRC, Ethiopia, Nigeria and Pakistan." • "GAVI supports vaccine costs for MR catch-up SIAs." • 80. • "Our analysis of operational costs of SIAs represents a minority of the total SIAs conducted worldwide over the analytical period. For example, our analysis of country-specific plans covered around 11% (41/360) of the measles/rubella-containing vaccine follow-up and catch-up SIAs conducted anywhere in the world between 2004 and 2011. Since mainly GAVI (eligible and graduating) countries report their immunization expenditures in cMYPs [comprehensive Multi-Year Plans], it is likely that our estimates represent a meaningful summary for this segment of countries, rather than more broadly. Similarly, because cMYPs are not produced by AMR [WHO Region of the Americas] countries, the analysis of country plans is not necessarily reflective of the situation in the Americas. Finally, looking the literature and budget data available, these are heavily skewed towards the AFR [WHO African Region] region (where the majority of SIAs have historically been conducted) which also limits the applicability of these findings to other regions." Gandhi and Lydon 2014, pp. 11-12. • "cMYP data are not systematically validated and may be of variable quality. It is difficult to know what is included in each country’s cMYP estimate of SIA operational costs since breakdowns by cost components are not provided." Gandhi and Lydon 2014, p. 13. • 81. • "The primary source for this analysis was country-specific data from cMYPs submitted to the WHO and the United Nations Children’s Fund (UNICEF) in 2009 and 2011. cMYPs are used mainly by immunization program managers in LICs [low-income countries] and MICs [middle-income countries] to articulate a long-term costed plan for a national immunization program." Gandhi and Lydon 2014, p. 4. • "The extracted baseline cMYP data constitutes 142 SIA country observations of SIA operational costs from 70 cMYPs produced by 40 countries; i.e. several countries developed more than one cMYP, and several countries conducted more than one SIA over the analytical period. Of the 142 observations, 75 are from the period 2004– 2007 while 67 are from the period 2008–2011. The distribution of the data by vaccine is illustrated in Figure 1." Gandhi and Lydon 2014, p. 4. Figure 1 shows 38 expenditure estimates from measles SIAs and three from MR SIAs. • See the cMYP data set in Additional File 1 of Gandhi and Lydon 2014 Additional files (xlsx). • 82. See Gandhi and Lydon 2014, Table 2, p. 9. We have inflation-adjusted the reported values from 2010 USD to 2015 USD. • 83. See Gandhi and Lydon 2014, Figure 4, p. 12 for breakdown by region. We have inflation-adjusted the reported values from 2010 USD to 2015 USD. • 84. See Gandhi and Lydon 2014 Additional files (xlsx), sheet "SIA budget breakdown data". • 85. Gandhi and Lydon 2014, p. 3. • 86. See Gandhi and Lydon 2014, pp. 6-7, Table 1, for summary of the literature review findings. • 87. "Comparing results in Table 2 versus Table 1 in general, as well as on a country-specific basis (in the penultimate column of Table 1), operational costs from the new analysis of country plans are generally higher than published estimates." Gandhi and Lydon 2014, p. 9. • 88. "1.2. Operational costs$351 million of the total $596 million measles and measles rubella follow-up campaign costs "This sub-category represents costs associated with follow-up SIAs, including planning, training, communication and social mobilization, transport and logistics, waste management, human resources, monitoring and supervision. These activities are essential to ensure that campaigns are of high-quality and that children have access to safe and effective vaccines which their parents demand. "M&RI funds up to 50 percent of the operational costs for follow-up SIAs. M&RI requires that countries finance the other 50 percent of the operations costs. Countries are able to raise the balance from either government budget and/or in-country partner resources. For Gavi-supported SIAs, Gavi provides$0.65 per target individual – equaling 69 percent of operational costs – and government and other partners are expected to cover the balance. Operational costs for M&RI in 2015 were calculated at $0.94 per target individual. Operational costs are projected to increase by 3% annually." Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p.18. • 89. • "The information documented in both existing literature and possibly the data from cMYPs may not be reflective of the full costs of implementing an SIA. In addition to the operational costs incurred mainly by national payers and reported in the literature and cMYPs, implementation of SIAs that are part of global ADC/E/E [accelerated disease control, elimination, and eradication] efforts often rely on additional expertise from global agents such as WHO, UNICEF, and the United States Center for Disease Control and Prevention (US CDC). [...] The costs associated with these additional support activities are often referred to as 'core costs' in agency budgets but are rarely factored into estimates of operational cost estimates to illustrate the true nature of SIAs." Gandhi and Lydon 2014, p. 12. • Our information on the costs of SIA support activities covered by international partners comes from the Measles and Rubella Initiative Annual Report 2013 and the Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015. • 90. For M&RI's published budget, see "Table 1: Summary of Resource Requirements by Major Category of Activity, 2015-2020 (All Figures in US$ Millions)", Measles and Rubella Initiative Financial Resource Requirements 2015-2020 as of Oct. 2015, p. 15. Our estimate is based on a previous, unpublished version of this table which reported the estimated number of persons reached via these activities.

• 91.

Areas with high measles burden (in terms of cases and fatality) and low rates of routine immunization.

• 92.

The cost-effectiveness of SIAs is highly sensitive to several inputs about which we have limited information. We provide this rough cost-effectiveness analysis of various scenarios for this program only to illustrate that measles SIAs seem to be potentially as cost-effective as our other priority programs in some countries: GiveWell's interim cost-effectiveness analysis of measles SIAs. Note that since this cost-effectiveness analysis is preliminary, it does not include many adjustments that we would typically include in a finalized cost-effectiveness analysis, and hence is not directly comparable to the cost-effectiveness analyses that we have produced for programs run by our top charities.

• 93.

While we have not seen compelling evidence that campaigns targeting older children cost-effectively prevent additional deaths, we have considered two major ways in which they might do so:

1. SIAs targeting older children might have sufficient impact on measles transmission to cost-effectively prevent infections in children under five, and hence deaths in this age group. While the most straightforward way to protect children under five is by immunizing them directly, vaccination does not reliably produce immunity in children under 6 months and appears to be only 85% effective among 9-month-olds, compared to 95% effectiveness among children over 12 months old. Hence, there is an age gap in which an infant is potentially susceptible to measles, and some infant deaths may be prevented indirectly by reducing the transmission rate of measles virus to this susceptible population.

M&RI, among others, argues that successful efforts to reduce measles incidence in young children have shifted the disease burden towards school-aged children, and that a reservoir of unimmunized school-aged children (who have high rates of epidemiological contact) risks transmission to younger siblings at home. GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016, p. 3.

We are pessimistic about the potential for SIAs to have a large effect on infant deaths via interrupted transmission. While we are not aware of any attempts to estimate this effect and have not seen evidence that would enable us to estimate it, our best guess is that the reduction in transmission would not be large enough for campaigns targeting older children to be as cost-effective as our other priority programs. Two (somewhat contradictory) major factors contributing to our pessimism are:

• Our impression is that in areas of high measles transmission, school-aged children are likely to be immune to measles due to surviving the virus in infancy or prior immunization.

While we have been unable to find studies of how the risk of measles infection varies with the proportion of the population immunized, we have seen it commonly assumed that annual risk of measles infection in populations that have not achieved high levels of immunity remains at 'pre-vaccination era' levels of about 30% per year. At 30% risk of infection per year, a child has an 83% chance of catching measles before age five (without considering the impact of measles mortality). Because surviving measles confers immunity, in areas of high measles transmission we would expect most children to have acquired immunity by age five even in the absence of any vaccination efforts. Routine vaccination and vaccination from prior campaigns further increases the proportion of older children who are already immune to measles.

The WHO Measles Strategic Planning Tool model of measles infection illustrates estimated probability of infection with the following figure:

Simons et al. 2011, p. S29-S30.

• SIAs would need to achieve very high levels of immunization coverage (≥95% in all districts) to interrupt measles transmission. SIA coverage surveys and the ongoing cycle of measles transmission and outbreaks in priority countries with SIA programs suggest that past SIAs in these countries have not successfully achieved sufficiently high coverage levels to interrupt transmission.
2. SIAs targeting older children might have sufficient impact on measles transmission to accelerate progress towards measles elimination or near-elimination, saving significant costs of measles control in the future. Global models of the cost-effectiveness of measles immunization (for example, Bishai et al. 2010, Levin et al. 2011) count cost-savings from reduced future measles control activities as offsetting the near-term costs of measles control.

In some contexts, it appears that SIAs are highly effective in contributing to elimination or near-elimination of measles: for example, in the Americas, mass immunization campaigns appear to have been instrumental in reducing confirmed yearly cases from >250,000 in 1980 to zero in 2003 (Castillo-Solorzano et al. 2011, p. S271). Although it is difficult to isolate the effect of rising routine coverage (black line), mass immunization campaigns (vertical arrows) appear to effect sharp drops in measles cases (red bars). The graphic is from Castillo-Solorzano et al. 2011, p. S275.

However, as discussed above, we are uncertain about the track record of measles SIAs in current M&RI priority contexts in achieving very high coverage rates and successfully interrupting measles transmission. We are especially uncertain about the availability of evidence which could inform estimates of the impact of particular SIAs or SIA programs on future cost savings.

• 94.
• 95.

"Current estimates of CFRs [case fatality ratios] used by the World Health Organization (WHO) in low-income countries range between 0.05% and 6%. In complex emergencies or isolated areas where there is either low natural immunity or low vaccination coverage, the CFR is often between 10% and 30%. Little research has explored the epidemiologic data to support these estimates and few comprehensive studies are reported in the published literature." Wolfson et al. 2009, p. 192.

The case fatality ratio estimates in Wolfson et al. 2009 p. 202, ranging from 0.05%-6%, are explicitly for children under five: "Based on the findings of this review, an expert group was constituted to categorize countries by similarity of factors that influence CFR, and derived a set of CFR ranges among children aged 1–4 years, for use in determining the global burden of measles (Table 2)." Wolfson et al. 2009, p. 201.

• 96.

In 2015, GBD Compare - total measles deaths estimates that there were about 62,588 global measles deaths in children under 5 and about 9,203 global measles deaths in children 5 to 14 years old. There were far fewer measles deaths in people aged 15 or older (roughly 1,654 total). Hence, GBD Compare - total measles deaths estimates that roughly 85% of global measles deaths were among children under five.

• 97.

"Gavi restricts its measles campaign funding for measles follow-up vaccination campaigns to children under 5. Dr. Cochi explains that this is because Gavi currently has established a funding ceiling and prioritizes younger children as this age group has a higher likelihood of dying of measles." GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016, p. 2.

• 98.
• 99.

"M&RI’s 2015-2020 funding gap was approximately $430 million. It is in the process of preparing an updated 2016-2020 budget taking into account the new Gavi funding, which will close the gap by approximately$130 million. This leaves M&RI with a fundraising target of approximately \$300 million for this 5-year period." GiveWell's non-verbatim summary of a conversation with Steve Cochi and Elesha Kingshott on January 12, 2016, p. 3.

• 100.