Measles Elimination in the Americas:A Comparison of Countries With a One-

dose and Two-dose Routine Measles Vaccination Schedule

Adrianne Sever, MDEpidemic Intelligence Service Officer

Global Immunization Division

January 29, 2009

Presentation Overview

• Background• Study Objectives• Methods Overview• Results• Limitations• Discussion• Conclusions

PAHO Strategy• All Countries:

• “catch-up” campaigns—ages 1-14 yrs.• “keep-up” routine vaccination coverage

• High (≥95%) first-dose coverage at 12 months of age

• “follow-up” campaigns—ages 1-4 yrs.

• Some countries:• 2nd routine dose (MCV2) at 4-6 yrs.

Routine Measles Vaccination Schedule by Country 1992-2002

*El Salvador introduced MCV2 in 1999, but after the last measles case

Excluded from Analysis

1-Dose

2-Doses

Study ObjectivesUsing available data from the PAHO region:1) To identify if socioeconomic, demographic

and programmatic differences existed between countries with a one-dose and two-dose routine vaccination schedule (background)

Then:2) To assess if a 2nd routine dose had an effect

on time to elimination

Analytic Overview

Descriptive Analysis

Propensity Score-Matching

Survival Analysis

To evaluate characteristics of one and two-dose countries in the region

A method to reduce bias by identifying a subset of countries with similar

characteristics

To assess if time to elimination differed between countries with a one-dose and

two-dose schedule

Method Purpose

Study ObjectivesUsing available data from the PAHO region:1) To identify if socioeconomic, demographic

and programmatic differences existed between countries with a one-dose and two-dose routine vaccination schedule (background)

Then:2) To assess if a 2nd routine dose had an effect

on time to elimination

Methods: Objective 1General characteristics of countries

• Definitions:• “Two-dose country”: had a 2-dose routine

vaccination schedule prior to interruption of measles virus transmission

• “One-dose country”: had a one-dose routine vaccination schedule or a second routine dose was added after endemic virus transmission was interrupted

• Means and medians of one-dose and two-dose countries were compared using 95% CIs and the Kruskal-Wallis test (alpha level of 0.05)

VariablesVaccination Program

1999-2001**

• MCV1 Coverage• SIA Coverage• DTP 1 Coverage• DTP3 Coverage• Measles Dropout• DTP Dropout• Surveillance Quality

Demographic & Socioeconomic 2000*

• Population Density• Female Literacy• Gross National Income (GNI) per Capita• Proportion Urban Population• Percent GNP Spent on Healthcare• Infant Mortality• School Attendance• Aggregate Doctor and Nurse Ratio

*Data from the year 2000 or for the last year it was available**Coverage averaged over 1999-2001, or average of 3 campaigns

Comparison of Demographic and Socioeconomic Variables

2-Dose Countries (N=7)

1-Dose Countries (N=14)

Variable Mean (95% CI) Mean (95% CI)Infant mortality (per 1000 live births)*

17 (12-22) 33 (25-42)

Proportion urban population (%)* 76 (63-89) 60 (51-68)

Female literacy (%)* 94 (91-97) 80 (72-88)

GNI per capita (USD)* 473 (309-637) 335 (191-479)

Percent of GDP spent on health Care*

7 (6-9) 6 (6-7)

Net primary school enrollment (%)**

90 (79-100) 86 (75-98)

Doctor and nurse ratio (per 10,000 population)*

97 (86-108) 92 (81-104)

Population density(people per km2)*

37 (17-58) 86 (29-144)

•Source: PAHO Basic Indicators http://www.paho.org/English/SHA/coredata/tabulator/newTabulator.htm**Source: UNESCO database http://stats.uis.unesco.org/unesco/TableViewer/document.aspx?ReportId=143&IF_Language=eng

Comparison of Immunization Program Variables

2-Dose Countries(N=7)

1-Dose Countries(N=14)

Variable Mean (95% CI) Mean (95% CI)

MCV1 coverage 91 (85-97) 92 (88-96)

Measles SIA coverage 88 (80-95) 91 (89-94)

DTP1 coverage 95 (92-97) 93 (90-97)

DTP3 coverage 87 (80-94) 83 (74-92)

Measles dropout rate 4 (-3-11) 6 (1-11)

DTP dropout rate 7 (0-13) 12 (6-19)

Surveillance quality* 80 (62-99) 84 (75-94)

Source: Country reports to PAHO-WHO/UNICEF *Percent of sites reporting weekly to PAHO, 1999-2001

Summary of Descriptive Analysis

• High MCV1 and SIA coverage overall

• Two-dose countries:• Higher proportion urban population • Higher female literacy • Higher GNI per capita • Lower infant mortality

Study ObjectivesUsing available data from the PAHO region:1) To identify if socioeconomic, demographic

and programmatic differences existed between countries with a one-dose and two-dose routine vaccination schedule (background)

Then:2) To assess if a 2nd routine dose had an effect

on time to elimination

Methods Used for Assessing if a Second Routine Dose had an Effect on Time to

Elimination

• Propensity Score Matching

• Survival Analysis

• Measles Susceptibility Estimates

Propensity Score Matching

Propensity Score Matching Methods• Why: Good approach for reducing selection bias

when you have a small sample size

• What: Method for equating covariates (potential confounders) of two comparison groups

• How: Model the conditional probability of exposure (one-dose vaccination schedule) given covariates

• Outcome: Model produces a score that represents a summary of covariates

• Then what: Conduct final analyses using countries with similar propensity scores

2 Propensity Score Models“partial model”—6 variables• MCV1 coverage • measles SIA coverage• measles SIA schedule• population density• percent urban population• surveillance quality

“ full model”—13 variables• MCV1 coverage • measles SIA coverage• measles SIA schedule• population density• percent urban population• surveillance quality• DTP 1 coverage• DTP3 coverage• female literacy• GNI per capita • % GNP spent on healthcare• infant mortality• school attendance

Propensity Score Matching: “Partial Model”

Country Propensity ScorePeru 0.66Brazil 0.66Cuba 0.66

Venezuela 0.48

Belize 0.82Bolivia 0.73DR 0.78Ecuador 0.73El Salvador 0.81Paraguay 0.83

Guatemala 0.87Haiti 0.89Honduras 0.89Nicaragua 0.89

Country Propensity ScoreChile 0.61

Panama 0.48Uruguay 0.50Argentina 0.43

Costa Rica 0.78

Colombia 0.36Mexico 0.35

1-dose countries 2-dose countries

Propensity Scores Summary

• “partial model” : 15 matched countries to include in final analysis

• “full model” : no matched countries• Propensity scores:

• One-dose countries: 0.61-0.92• Two-dose countries: 0.14-0.46

• Lack of matching was likely due to differences in socioeconomic and demographic variables

Survival Analysis

• Kaplan-Meier Curves

• Crude analysis (21 countries)

• Propensity score-matched analysis (15 countries)

• Time to elimination

• 1992 Start date

• 3 definitions

• Case-based

• Population-based

• Combination

Survival Analysis: Time to Elimination

Elimination Year Definitions

• Case-based--the year following the last endemic (non-imported) measles case up through 2002

• Population-based--the year that measles incidence of < 1 lab-confirmed cases/1 million was achieved and sustained

• Combination--the later of the two years of the definitions above

Crude Survival Analysis: Time to Measles Elimination

χ2 =0.07, p=0.79

Perc

ent o

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Elim

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Propensity Score-Matched Survival Analysis: Time to Elimination

χ2 =0.44, p=0.51

Perc

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Elim

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Measles Susceptibility

Measles Susceptibility Methods

• Estimated measles susceptibility for each country for birth cohorts under 15 years of age using:

• MCV1 coverage• SIA coverage x 3 campaigns• MCV2 coverage: assumed 0%, 50%, and 75%

coverage• Vaccine Efficacy: 85% in first year, 95% in

second year or older

0102030405060708090

100

Mean Measles Susceptibility by One-dose and Two-dose Countries

1-Dose Countries

N=14

2-Dose CountriesN=7

Pro

porti

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son

unde

r 15

susc

eptib

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mea

sles

(%)

0% 50% 75%

Proposed Immunity Threshold

(<7% Susceptible)

MCV2 Coverage Assumptions

Question 2 Summary• “Partial model” matched 15 countries with

similar characteristics • Crude and propensity score-matched

survival analyses showed no difference in time to elimination

• Measles susceptibility after MCV1 and campaign doses was low for both groups and near the proposed herd immunity threshold

Limitations

• Ecologic analysis• Small number of observations (countries)• Could not reduce all possible bias• MCV2 coverage data not included in analysis • MCV2 age of introduction differs from other

regions (may not be applicable)

Discussion• The second routine measles dose had no

apparent impact on time to elimination• High first dose and campaign coverage• At threshold immunity level without MCV2• MCV2 given at 4-6 years of age, after most

children had received a second opportunity

• Campaigns occurred simultaneously throughout region

Public Health Implications

• In PAHO, where countries have high routine and campaign coverage, a second routine dose did not effect time to measles elimination when introduced at school entry.

• Successful vaccination program implementation was more important than the underlying socioeconomics of a country in eliminating measles.

Future Research

• Apply similar methods using data from other regions

• Assess MCV2 impact on sustaining elimination

Acknowledgements

• CDCDr. Vance DietzDr. Jeanette RaineyDr. Elizabeth ZellDr. Karen HennesseyDr. Amra UzicaninDr. Steve CochiDr. Hardeep Sandhu

• PAHODr. Carlos Castillo-SolorzanoDr. Jon AndrusDr. Carolina DonavaroMs. Christina MarsigliMs. Pamela Bravo

Thank You!

Extra slides

Methods: Country Classification

Country Vaccination Policy MCV2 Date Case-based Elimination YrPanama Two-dose 1992 1996Costa Rica Two-dose 1992 2000Chile Two-dose 1992 2000Uruguay Two-dose 1992 2000Colombia Two-dose 1997 2002Argentina Two-dose 1998 2001Mexico Two-dose 1998 2001El Salvador One-dose 1999 1997Brazil One-dose 2004 2001Paraguay One-dose 2004 1999Cuba One-dose 2004 1996Belize One-dose 2005 1996Guatemala One-dose NA 1999Honduras One-dose NA 1998Nicaragua One-dose NA 1996Venezuela One-dose NA 2002Peru One-dose NA 2001Ecuador One-dose NA 1997Bolivia One-dose NA 2001Dominican Republic One-dose NA 2002Haiti One-dose NA 2002

Summary of Immunization Program Indicators

Indicator Mean (95% CI) Median (Range)

MCV1 Coverage 92 (89-95) 94 (73-99)

Measles SIA Coverage 90 (87-93) 93 (77-97)

DTP1 Coverage 94 (91-96) 96 (77-98)

DTP3 Coverage 84 (79-90) 88 (45-99)

Measles Dropout Rate 5.6 (1.7-9.4) 3.2 (-6.7-28.6)

DTP3 Dropout Rate 7.3 (5.8-14.9) 7.3 (0-41.6)

Surveillance 82 (74-90) 90 (44-100)

Summary of Socioeconomic and Demographic Indicators

Indicator Mean (95% CI) Median (Range)Population density (people per km2)* 70 (32-109) 41 (7.7-303)

Percent urban population* 65 (58-73) 60 (50-92)Literacy rate* 86 (81-92) 92 (50-98)GNI per capita* 383 (278-488) 364 (100-860)Percent of GDP spent on Health Care** 6.6 (6.0-7.2) 6.5 (4.4-10.1)Net Primary School Enrollment 87 (80-95) 90 (21-99)

Doctor and Nurse Ratio (per 10,000 population) 94 (86-102) 96 (27-107)

Infant Mortality Rate 28 (21-35) 28 (7.5-62)

*Data for the year 2000** Last available data (not collected yearly

Summary of comparison of indicators* versus last confirmed case

*Each indicator was broken down into specific categories

Indicator Categorization of Indicators

Mean MCV1 CoverageMean of 1999-2001 ( 1>=95%, 2=90-94%, 3=80-89%, 4=<80%)

SIA CategoryClassification of countries as to whether SIAs were held every 4-6 years, (1=4-6 yrs, 2= >6 yrs)

SIA CoverageVaccination coverage of SIAs (Average of 3 campaigns) (1>=95%, 2=90-94%, 3=80-89%, 4=<80%)

Population Density People per km2 for year 2000 (quartiles)

GNI per Capita Gross National Index per capita for the year 2000 (quartiles)

Proportion Urban Population Proportion Urban population for the year 2000 (quartiles)

Infant Mortality Infant Mortality for 2000 (per 1000 persons) (quartiles)

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1995

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MCV

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2-dose countries 1-dose countries 2-dose countries 1-dose countries

Measles Cases and MCV1 Coverage among countries with 1 or 2 doses* of MCV1, Region

of the Americas 1994-2002

*Over time, new countries introduced MCV2 at which point that country moved from one-dose to 2-dose country category

Methods: Question 2 Were any variables independent predictors of

elimination?

• Bivariate analysis• Variables were categorized

- A priori knowledge (immunization program)- Quartiles (socioeconomics and demographics)

• Outcome Categories: Early (<2000) vs. Late (≥2000)

•

Question 2: Results and Summary

• Surveillance quality (p=0.03) only variable significantly (p<0.05) associated with measles elimination

• Percent urban population (p=0.05) approached significance

Summary of comparison of indicators* versus last confirmed case

Fisher's Exact

Indicator (table probability) P-value

MCV1 Coverage 0.04 0.61

SIA Coverage 0.03 0.49

SIA Category 0.34 1.00

Population Density 0.03 0.78

Percent Urban Population 0.002 0.05

Infant Mortality Rate 0.03 0.57

GNI per Capita 0.005 0.17

*Each indicator was broken down into specific categories

Propensity Scores: 13 variable model

Demographic & Socioeconomic Variables

• Population density• Literacy rate• GNI per capita• Proportion urban population• % GNP spent on healthcare• Infant mortality• School attendance

Program Variables

•MCV1 coverage•SIA category•SIA coverage•DTP 1 coverage•DTP3 coverage•Surveillance

Propensity Scores- “Full Model”1-Dose Countries

Country Propensity ScoreVenezuela 0.61Cuba 0.77El Salvador 0.77Peru 0.78Belize 0.80DR 0.80Brazil 0.83Guatemala 0.88Nicaragua 0.88Haiti 0.89Bolivia 0.90Ecuador 0.92Honduras 0.92Paraguay 0.92

2-Dose CountriesCountry Propensity Score

Uruguay 0.14Mexico 0.18Argentina 0.21Colombia 0.26Panama 0.33Costa Rica 0.39Chile 0.46

Mean and median time to elimination* for 1-dose and 2-dose countries

*From 1992 to PAHO declaration of Measles Elimination in 2002

Doses # of countries Mean 95% CI Median Min:Max

1-Only 14 7.2 5.8-8.6 7.5* 4.0:10.0

2-Early** 4 7.0 3.8-10.2 8.0* 4.0:8.0

2-Late*** 3 9.3 7.9-10.7 9.0* 9.0:10.0

All 2-Dose 7 8.0 6.2-9.8 8.0**** 4.0:10.0

All 21 7.5 6.5-8.5 8.0 4.0:10.0

*X2 = 3.19, p-value = .20 (no statistical difference, using Kruskal-Wallis test)** Early introduction refers to countries that introduced in 1992***Late introduction refers to countries that introduced in 1997-1998****X2 = 0.24, p-value = .62 (no statistical difference, using Kruskal-Wallis test)

*1992 chosen as start point since year of first two-dose schedule in region

Survival Analysis: 1-dose vs. early and late 2-dose

0.00

0.25

0.50

0.75

1.00

1992 1994 1996 1998 2000 2002

1 dose measles schedule

2 dose measles schedule – early introducers2 dose measles schedule – late introducers

Time to Elimination

Time to elimination similar (X2 = 0.27, p-value =0.26)

Secondary Outcome: Susceptibility

Susceptibility under 15 years of age

Routine MCV Vaccination

Schedule Mean (%) (95% CI)

Median

1-dose countries 7.4 (5.5-9.2)

2-dose countries0% MCV2 coverage 5.9 (3.9-7.9) 5.5

50% MCV2 coverage 4.1 (2.3-5.8)* 3.575% MCV2 coverage 3.3 (1.5-5.0)* 2.5

7.1

* statistically significant

Acknowledgement

This project is a collaborative effort with PAHO, and we would like to thank Dr. Carlos Castillo-Solorzano, Dr. Jon Andrus, Dr. Carolina Danovaro, and Ms. Christina Marsigli for their contribution and help with the project.

Objectives…cont.

• This study was designed to address whether a second routine dose had added benefit in measles elimination

• While new questions have been raised, i.e., if a second routine dose aids in sustaining measles elimination, we did attempt to asses this

• IS THIS EVEN NEEDED??

Mean Measles Susceptibility by one and two-dose countries

N=8

N=13

***

*Assuming 50% coverage for MCV2**Assuming 75% coverage for MCV2

Pro

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5 su

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to m

easl

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)

Propensity Score Matching Methods• Why: Good approach for small sample size

or where there is no control group

• What: Estimates the probability of exposure given a set of possible covariates

• How: Model the conditional probability of exposure (one-dose vaccination schedule) given potential covariates

• Outcome: “Summary” score with balanced covariates to reduce bias

• Then what: Match 1-dose country and 2-dose country propensity scores +/- 5%; countries with matching propensityscores used in final analysis

0

20004000

60008000

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1200014000

16000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Year

Num

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f Mea

sles

Cas

esConfirmed Measles Cases, the

Americas, 1998-2007

Measles Elimination

Introduction of 2nd Routine Measles Vaccine Dose by Country

1990 Never92 98 04 0894 96 2000 02 06

ChilePanamaUruguayCosta Rica

Colombia

ArgentinaMexico

El Salvador

BrazilCubaParaguay

Belize

BoliviaNicaraguaHondurasPeruDREcuadorVenezuelaGuatemalaHaiti

*includes Caribbean countries

Case-Based Elimination Year

1990 92 94 96 98 2000 02 04 06 08

NicaraguaCubaPanamaBelize

Honduras

GuatemalaParaguay

UruguayCosta RicaChile

BoliviaPeruArgentina

El SalvadorEcuador

ColombiaHaitiDR

BrazilMexico

Venezuela

Propensity Score Matching

Matching Algorithms• Nearest neighbor matching• Caliper/Radius matching• Stratification/Interval matching• Kernel & local linear weights• Weighting

Assess balance between groups one matched

Results: Immunization Program Variables

2-Dose Countries 1-Dose Countries

Variable Mean (95% CI) Median (Range) Mean (95% CI) Median (Range)

MCV1 Coverage 91 (85-97) 94 (80-96) 92 (88-96) 94 (73-99)

Measles SIA Coverage 88 (80-95) 91 (77-97) 91 (89-94) 94 (77-97)

DTP1 Coverage 95 (92-97) 94 (92-98) 93 (90-97) 96 (77-98)

DTP3 Coverage 87 (80-94) 88 (74-98) 83 (74-92) 87 (44-99)

Measles Dropout Rate 4.3 (-2.9-11) 3.2 (-6.7-19) 6.2 (1.0-11) 3.1 (-5.7-29)

DTP Dropout Rate 6.7 (0.45-13) 3.3 (1-20) 12.2 (5.7-19) 10.3 (0-42)

Surveillance Quality* 80 (62-99) 90 (44-97) 84 (75-94) 91 (48-100)

Source: Country reports to PAHO-WHO/UNICEF *Percent of sites reporting weekly to PAHO, 1999-2001

Results: Socioeconomic and Demographic Variables

2-Dose Countries 1-Dose CountriesVariable Mean (95% CI) Median (Range) Mean (95% CI) Median (Range)Population density (people per km2)*

37 (17-58) 40 (13-77) 86 (29-144) 43 (7.7-303)

Proportion urban population (%)*

76 (63-89) 75 (56-92) 60 (51-68) 58 (36-87)

Female literacy (%)* 94 (91-97) 96 (89-98) 80 (72-88) 84 (48-97)

GNI per capita (USD)* 473 (309-637) 486 (206-747) 335 (191-479) 217 (100-860)

Percent of GDP spent on Health Care*

7.3 (5.7-8.9) 7.0 (5.1-10.1) 6.2 (5.7-6.8) 6.4 (4.4-7.7)

Net Primary School Enrollment (%)**

90 (79-100) 90 (67-99) 86 (75-98) 91 (21-98)

Doctor and Nurse Ratio (per 10,000 population)*

97 (86-108) 96 (72-107) 92 (81-104) 98 (27-104)

Infant Mortality (per 1000 live births)*

17 (12-22) 18 (9-23) 33 (25-42) 32 (7.5-62)

•Source: PAHO Basic Indicators http://www.paho.org/English/SHA/coredata/tabulator/newTabulator.htm**Source: UNESCO database http://stats.uis.unesco.org/unesco/TableViewer/document.aspx?ReportId=143&IF_Language=eng

Mean Measles Susceptibility by One-dose and Two-dose Countries

012

34567

89

10

1-Dose Countries

N=14

2-Dose CountriesN=7

Pro

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mea

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(%)

0% 50%* 75%**

Estimated Herd Immunity Threshold

*Assuming 50% Coverage fro MCV2**Assuming 75% Coverage for MCV2