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Transcript of Programmatic use of serologic biomarkers to monitor the quality of immunization services Rockville,...
Programmatic use of serologic biomarkers to monitor the quality of
immunization services
Rockville, MD, July 24, 2015
Myron M. (Mike) Levine, M.D., D.T.P.H.
Simon & Bessie Grollman Distinguished ProfessorAssociate Dean for Global Health, Vaccinology &
Infectious Diseases,University of Maryland School of Medicine,
Baltimore, MD, USA
UN Millennium Development Goal # 4 aims to diminish mortality in children < 5 years of age by 67% by 2015
Of the 35 countries with thehighest under-five mortality,32 are in sub-Saharan Africa!!!
(State of the World’s Children, UNICEF 2014)
The Expanded Program on Immunization (EPI)
Getting vaccines to those who need them
EPI clinic, Mali
Gavi – the vaccine alliance*
Access EquityInvestment
* Originally called the Global Alliance for Vaccines and Immunization (GAVI)
Current realities for immunization services in developing countries Current realities for immunization services in developing countries
• Most vaccines require 3 doses• Most vaccines are administered
parenterally• Most vaccines are sensitive to
either excessive heat or to freezing
• Expensive new vaccines are typically supplied in single-dose vials
EPI vaccines for infants, 2014EPI vaccines for infants, 2014Target Age Vaccine• Birth BCG, OPV, HBV+
• 6, 10 & 14 wks* Pentavalent (DwPT/Hib/HBV)• 6, 10 & 14 wks* Pneumococcal conjugate• 9 (to 12$) mos**Measles• 6, 10 & 14 wks* Oral polio vaccine• 6, 10 & 14 wks* Oral rotavirus vaccine+ Where seroprevalence is high & mother to infant transmission occurs* Given at 8, 16 & 24 weeks of age in Latin America and much of Asia$ Where measles control is good and disease in infants is uncommon** A 2nd dose of vaccine in 2nd year of life is becoming routine** In some countries, yellow fever, rubella or Japanese B vaccine also given
Invasive Hib burden,Bamako, Mali
Invasive Hib burden,Bamako, Mali
Among infants age 4-11 months admitted to hospital:
• 12% of all hospital admissions were due to invasive Hib disease
• 19.3% of deaths were due to Hib
S Sow et al, Pediatr Infect Dis J 2005
Age group
Year 1 Year 2 Year 3Mean Annual
0-1 m 21.9 10.6 10.3 14.22-3 m 22.3 43.4 63.4 43.44-5 m 133.1 270.7 263.3 223.6
6-7 m 411.5 341.4 377.8 376.68-9 m 175.2 275.2 446.1 301.310-11 m
134.7 117.9 127.5 126.6
0-11 m 145.5 171.0 206.5 174.9
Incidence of invasive Hib disease per 100,000 7/2002 - 6/2005
(S Sow et al, Pediatr Infect Dis J 2005)
Testing sera for IgG anti-Hib PRP antibodies - 1
• A high titer of IgG PRP antibody (> 1.0 mcg/ml) in infants 6-8 months of age constitutes a sensitive and specific objective indicator of:– timely immunization with 2 or 3 doses of
pentavalent vaccine (which contains Hib conjugate), and;
– enduring protection against invasive Hib disease.
• Timeliness of pentavalent immunization is critical to protect young infants against pertussis and invasive Hib disease.
Impact of Hib vaccine introduction on invasive Hib disease in infants,
Bamako, Mali
12-month Transition
Period,7-05 to 6-06
23-month Intervention Period, 7-06 to 5-08
36-month BaselinePeriod,
7-02to 6-05
Invasive Hib cases/105 infants per 6-month intervals
88% reduction
S Sow et al 2009
Prevalence of serum Hib PRP antibodies in Malian infants 6-7 months of age before and 18 & 30
months after the introduction of Hib conjugate into the EPI for Malian infants
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%60.00%
70.00%
80.00%
90.00%
100.00%
Baseline 18 mos. 30 mos.
0.15 mcg/ml
1.00 mcg/ml
Serum antibody levels:
N=200 N=200N=201S Sow et al,AJTMH 2009
Serum PRN measles antibody titers in Malian infants of different ages, demonstrating the “window of vulnerability”
and the response to measles vaccine
M Tapia et al. AmJTMH 2005
Overview of antibody biomarker issues
• What antibodies should be measured?• What clinical specimens should be collected?
– Serum (gold standard)– Dried blood spots (DBS)
• no centrifugation needed in the field ; • no reverse cold chain needed
– Oral (crevicular) fluid (no sharps involved)• Are point-of-care (i.e., point-of-contact)
devices that give immediate readouts feasible?
The overarching goal --
The goal is to quantify the proportion of the target population that has objective serological evidence of being protected rather than just having been inoculated
Some explanations for “immunization failures” & other discrepancies
• Defective cold chain• Immunogenicity of the vaccine
– Even in industrialized countries, ~ 2-3% of children who receive their 1st measles vaccination do not develop PRN antibodies
• Residual maternal antibodies interfere with infant immune response (measles)
• Child responds immunologically but titer is below the protective “cut-off”
• Transcriptional errors
Linking serosurveys to immunization
coverage surveys
• Team Composition• Coordination between the
coverage survey and serosurvey teams
• Equipment needs• Detailed standard operating
procedures (SOPs)• Community buy-in:
– Participant benefits– Informed consent led by local
health workers
Pairing an Immunization Coverage Survey with a Serosurvey: making it work
Age group
Number of
woredas
Sample size in each
woreda
Tetanus Antitoxin
Measles Antibody
Hib PRP Antibody
12-23 months
3300
children Yes Yes -
6-8* months
3100
children Yes
Serosurveys linked to immunization coverage surveys in 3 districts (woredas) in Ethiopia
* This age group has not historically been used to assess immunization coverage. CVD has shown the utility of documenting high titers of Hib antibodies as evidence of receipt of pentavalent vaccine.3 collaborating teams: JSI (coverage survey); Ethiopian Public Health Institute (serosurvey) CVD, U of Maryland (serosurvey and reference laboratory)
Comparison of tetanus antitoxin
in 727 sera measured by
ELISA vs in vivo neutralization
assay(Simonsen et al
1986)
Hintalo Wajerate: pentavalent vaccine doses and tetanus antitoxin in toddlers 12-23 mos. of age
Toddlers with Coverage Survey record of
pentavalent vaccine@
GMT, tetanus
antitoxin
No. (%) of toddlers with tetanus
antitoxin titers> 0.15 IU/ml
3 doses (217 toddlers) 0.95 IU/ml 209/217 (96%)
2 doses (16 toddlers) 0.85 IU/ml 14/16 (88%)1 dose (5 toddlers) 0.75 IU/ml 4/5 (80%)238 toddlers total 227/238 (95%)
@ ”Coverage Survey record” indicates documentation of vaccination by immunization card or EPI register.
Assaieta: pentavalent vaccine doses and tetanus antitoxin in toddlers 12-23 months of age
Toddlers with Coverage Survey record of
pentavalent vaccine@
GMT, tetanus
antitoxin
No. (%) of toddlers with tetanus
antitoxin titers> 0.15 IU/ml
3 doses (57 toddlers) 0.89 IU/ml 52/57 (91%)
2 doses (9 toddlers) 0.22 IU/ml 6/9 (67%)1 dose (15 toddlers) 0.04 IU/ml 6/15 (40%)
81 toddlers total 64/81 (79%)@ ”Coverage Survey record” indicates documentation of vaccination by immunization card or EPI register.
Pentavalent vaccine coverage estimates in
infants 6-8 monthsof age,
a measure of the timeliness of
immunizations
Pentavalent vaccine-3 in toddlers 12-23 mos. of age: administrative coverage, coverage survey & serosurvey
Estimate Hintalo Arbegona Assaieta
Administrative (2013) 90% 86% 65%
JSI Coverage Survey:(Vacc. Card+ EPI Register
+ Maternal Recall)
229/263(87%)
103/251 (41%)
72/215 (35%)
Serosurvey:Number (%) with tetanus
antitoxin > 0.15 IU/ml
244/263(93%)
151/251(54%)
114/215(46%)
Hintalo Wajerate: pentavalent vaccine doses and PRP & tetanus antibodies in infants age 6-8 mos.
Coverage Survey record of Penta vaccine@
No. (%) of infants with:PRP titers
> 1.0 mcg/ml
3 doses (43 infants) 38/43 (88%)
2 doses (15 infants) 8/15 (53%)
1 dose (12 infants) 3/12 (25%)
70 infants total 49/70 (70%)@ ”Coverage survey record” indicates documentation of vaccination by either immunization card or EPI register.
DBS
Dried Blood Spots (DBS) in serosurveys
Good spots Poor quality spots
Correlation between tetanus antitoxin titers in DBS eluates vs. serum from toddlers age 12-23 months
r=0.91
Correlation between measles IgG antibody titers in DBS eluates vs. serum from the same 60 adult subjects
Measuring antibody in oral (crevicular)
fluid
Correlation of tetanus antitoxin titers measured in serum and oral fluid of 212 Malian subjects by IgG-ELISA
Tapia et al. Pediatr. Infect. Dis. J. 2006
r=0.90
Correlation of measles antibody titers in serum measured by PRN and in oral fluid by IgG-ELISA
Vertical line = protection level 120 mIU; n=212
r=0.88
Serum Measles Titer (mIU/ml)
Ora
l Flu
id M
easl
es T
iter
(m
IU/m
l)
10 100 1000 10000 1000001
10
100
1000
10000
r = 0.9281P < 0.0001n = 60
Correlation of measles antibodies measured by IgG-ELISA in serum and in oral fluid (US adults)
Correlation of measles antibodies in serum and inoral fluid measured by IgG-ELISA
Vertical line = protection level 120 mIU; n=212
r=0.92
BD Veritor™ System: Serosurvey Kit
BD Veritor™ System Serosurvey Tool30 Test KitFor Use with Oral (Gum) Swab
Specimens• Unitized Tubes with Dispense Tips
Pre-filled with assay diluent
• Pur-Wrap foam swabs – 30 each individually wrapped
Swab gums
Remove cap from unitized tube
Insert swab, swirl, remove swab
Attach dispense tip
Dispense three drops to sample well
Read in 10 minutes
Swab Sample Processing :
Tetanus Antitoxin Kits used in field trials in West Africa
Ethiopia project acknowledgments
EHNRISerosurveyBerhane BeyeneShitu HaileElfinesh DawwawTeklil BizaRajiha AbubekerEshetu LemmaTassew KassaMekonen GetahunNathanael DiresTamrat TadesseMenberu TedlaAngelo AshaBirke TeshomeAmha Kebede
CVDSerosurveyMark TravassosJames CampbellMarcela PasettiNigisti MulhollandInna RuslanovaJaya GoswamiKaren BallWilliam BlackwelderYukun WuMardi ReymannMyron M Levine
JSI Immunization Coverage Survey Zenaw Adam Anteneh Girma Lisa OotSamrawit AshenafiJenny SequeiraTewodros WoldetsadikRobert SteinglassEdris AbdellaHaileslassie TsegabuMeka Metekia
CVD MaliSeydou Diarra
Point-of-contact rapid assessment tool to detect protective titers of tetanus, measles and Hib
antibodies in oral (crevicular) fluidField site CVD-Mali, Bamako, Mali
PI Milagritos Tapia, MDCo-PI Samba O. Sow, MD, MSc
Co-InvestigatorsFatoumata Diallo, MD, Fadima Cheick Haidara, M D, Moussa Doumbia, MD, Flanon Coulibaly, MD, Auwa Traore, Pharm D, Uma Uonwuchekwa
Co-Investigators
Wilbur Chen, MD, Marcela Pasetti, PhD, William Blackwelder, PhD, Mardi Reymann, M.S.
Co-Investigator Michael Fiechtner, PhD, Rick Anderson, PhD
Coordinating Investigator Myron M. Levine, MD, DTPH
Thank you on behalf of the teams