Impact and Cost-Effectiveness of Haemophilus inuenzae Type b

Conjugate Vaccination in India

Andrew D. Clark, MA1, Ulla K. Griffiths, PhD1, Syed Shahid Abbas, MBBS, MPH2, Krishna D. Rao, PhD2,
Lois Privor-Dumm, MIBS3, Rana Hajjeh, MD4, Hope Johnson, PhD3, Colin Sanderson, MA, MSc, PhD1,
and Mathuram Santosham, MD, MPH3
Objective To estimate the potential health impact and cost-effectiveness of nationwide Haemophilus influenzae
type b (Hib) vaccination in India.

Study design A decision support model was used, bringing together estimates of demography, epidemiology,
Hib vaccine effectiveness, Hib vaccine costs, and health care costs. Scenarios favorable and unfavorable to the
vaccine were evaluated. State-level analyses indicate where the vaccine might have the greatest impact and value.
Results Between 2012 and 2031, Hib conjugate vaccination is estimated to prevent over 200 000 child deaths
(
1% of deaths in children <5 years of age) in India at an incremental cost of US$127 million per year. From a government perspective, state-level cost-effectiveness ranged from US$192 to US$1033 per discounted disability adjusted life years averted. With the inclusion of household health care costs, cost-effectiveness ranged from
US$155-US$939 per discounted disability adjusted life year averted. These values are below the World Health Organization thresholds for cost effectiveness of public health interventions.
Conclusions Hib conjugate vaccination is a cost-effective intervention in all States of India. This conclusion does
not alter with plausible changes in key parameters. Although investment in Hib conjugate vaccination would significantly increase the cost of the Universal Immunization Program, about 15% of the incremental cost would be offset
by health care cost savings. Efforts should be made to expedite the nationwide introduction of Hib conjugate vaccination in India. (J Pediatr 2013;163:S60-72).

uring the last decade 1 in every 10 children born in India died before reaching their fifth birthday, representing
around 20% of child deaths globally.1 A nationally representative mortality survey conducted in India between
2001 and 2003 (the Million Death Study) estimated that 16% of deaths of children <5 years of age were caused
by pneumonia and
4% by invasive bacterial diseases such as meningitis.2 Haemophilus influenzae type b (Hib), a bacterium transmitted from person to person by the respiratory route, is a leading cause of bacterial pneumonia in countries
where the vaccine is not used. Safe and effective national Hib conjugate vaccination programs are now implemented in
most countries worldwide, but introduction has been delayed considerably in India compared with other countries. In
June 2008, the Indian National Technical Advisory Group on Immunization recommended nationwide introduction of
Hib conjugate vaccination.3,4 It subsequently took 3.5 years to initiate phased introduction, starting in December 2011
with Tamil Nadu and Kerala, 2 states covering less than 5% of the national child mortality burden. To date, the vaccine
is yet to be introduced in any of the high mortality states.
Several challenges have contributed to the delayed introduction. In particular, there has been a lack of technical consensus on the public health need and cost-effectiveness of including the vaccine in the national immunization program.
In July 2005, a pilot Hib disease surveillance study was initiated to lay the groundwork for a large vaccine probe study to
document the burden of Hib disease in India and the impact of vaccination.5 The probe study was, however, never conducted, as it was judged unethical following a World Health Organization (WHO) position that conjugate Hib conjugate vaccines should be included in all routine infant immunization programs.6 Also, at this time, Hib conjugate
vaccines became widely available in the private sector in India and several

ALRI
CFR
DALY
DTP
GDP
Hib
NFHS
NPNM
WHO

Acute lower respiratory infection

Case fatality ratio
Disability adjusted life year
Diphtheria-tetanus-pertussis
Gross domestic product
Haemophilus influenzae type b
National Family Health Survey (also known as the Demographic and Health
Survey or DHS)
Non-pneumonia-non-meningitis
World Health Organization

From the 1Department of Health Services Research and

Policy, London School of Hygiene and Tropical Medicine,
London, United Kingdom; 2Public Health Foundation of
India, New Delhi, India; 3Johns Hopkins Bloomberg
School of Public Health, Baltimore, MD; and 4Division of
Bacterial Diseases, National Center of Immunization and
Respiratory Diseases, Centers for Disease Control,
Atlanta, GA
Supported by the Hib Initiative and funded by the GAVI
Alliance.
Please see the Author Disclosures at the end of this
article.
0022-3476/$ - see front matter. Copyright 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.03.032

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Indian manufacturers were producing the vaccine. The
only randomized controlled trial in Asia (Lombok Island,
Indonesia; 1998-2002) reported a preventable incidence of
both clinical pneumonia (1561 per 100 000 aged <2 years)
and meningitis (16 per 100 000 aged <2 years). Confusingly, however, the same study reported no preventable
burden of radiologic pneumonia.7 A case control study
(Dhaka city, Bangladesh; 2000-2003) reported a 32% protective effect against radiologic pneumonia. However, results from this study varied considerably depending on
who read the chest radiographs and whether the controls
were hospital- or community-based (16%-44%).8 The
mixed evidence from the region and the lack of strong evidence from India have made it difficult for country officials to make a decision about Hib conjugate vaccination,
and some local groups have argued against its inclusion in
the routine program.9 Where uncertainties exist and are
likely to continue to exist, decision support models can
help decision makers consider the potential impact and
cost-effectiveness of the vaccine under a range of plausible
favorable, and more importantly, unfavorable, assumptions.
In this analysis, a decision support model was used to
bring together the best available evidence and calculate,
for a broad range of scenarios, the impact and value
(cost-effectiveness) of Hib conjugate vaccination in India.
We estimated this for individual states and aggregated to
the national level over the period 2012-2031. With an annual birth cohort of
26 million, the Ministry of Health
and Family Welfare has to consider very carefully the economic implications of universal Hib conjugate vaccination. The aim of cost-effectiveness analysis is to help
decision-makers make investments in health interventions,
which provide good value for money when compared with
recognized benchmarks or competing health priorities.

This study estimate, the potential cost-effectiveness of nationwide Hib conjugate vaccination in India.

Methods
The decision-support model has been described in detail
elsewhere.10 In short, the model tracks the experience of
20 successive birth cohorts. Cost-effectiveness is based on
the aggregated costs and benefits over this sustained period
of routine vaccination (2012-2031) allowing key parameters
to vary over time. Vaccination program costs are assumed
to occur in the first year of each cohort. Disease cases,
deaths, and treatment costs are estimated for the first 5
years of age, but lost life-years, disability adjusted life years
(DALYs), and sequelae costs are estimated over expected
lifetimes. State-level estimates of numbers of births, infant
mortality, mortality of children <5 years of age, and lifeexpectancy were based on the 2001 census projections.11
State-level estimates of numbers of births were scaled to
be consistent with the national United National Population
projections (2008 Revision) for India.1 Estimates of neonatal mortality for each state were based on the 2005-2006 Indian National Family Health Survey (NFHS).12 Hib disease
is divided into 3 categories defined by the Hib global burden of disease project13: pneumonia, meningitis, and nonpneumonia-non-meningitis (NPNM) invasive diseases.
NPNM diseases, such as cellulitis and epiglottitis, were
grouped for simplicity because they are less common
than meningitis and pneumonia. The model structure is
shown in Figure 1. Outputs are compared with
a scenario with no Hib conjugate vaccination. The
analysis was undertaken from a societal perspective,
including costs incurred by the Indian Government, the
GAVI Alliance, and Indian households. Future program
costs, treatment costs averted, and health benefits were

Figure 1. Simplified structure of the Hib disease burden model.

Impact and Cost-Effectiveness of Haemophilus influenzae Type b Conjugate Vaccination in India

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discounted by 3% per year.14 We did not assume age

weighting on DALYs (ie, no greater preference was
assigned to life-years gained in the working age range).
Costs were estimated in 2010 US$ using an exchange rate
of 45.7 Indian rupees for one US$.15
Cases of Hib Meningitis, Deaths, and Sequelae
Between 1997 and 1999, a prospective hospital surveillance study in Vellore reported Hib to be the cause of
44% (8 of 18) of confirmed cases of bacterial meningitis, with
7 confirmed cases per 100 000 children aged
less than 5 years.16 Recent multicenter surveillance estimates from Vellore, Chennai, Lucknow, and New Delhi
suggest that 70% of bacterial meningitis may be caused
by Hib.17 We used the lower and more conservative estimate of 44%, but made adjustments to account for
cases of Hib that were not detected in the laboratory
and cases that did not have access to care. Because
57% (24 of 42) of the purulent (probable) cases had
no confirmed pathogen in the Vellore study, we assumed the percent of unconfirmed cases attributable
to Hib to be the same as the percent of confirmed cases
attributable to Hib (44%), based on WHO guidelines 18
and following methods used in other bacterial meningitis etiology studies.19 In addition, we assumed that 23%
of the cases would not have had access to formal medical care during this study based on the proportion of
children living in Vellore who, according to the
NFHS, did not seek care for acute lower respiratory infection (ALRI) in 2006.12 Hence, the final adjusted Hib
meningitis incidence was 22 per 100 000 children <5
years [7.12/(157%)]/(123%). We assumed this incidence estimate for all states.
State-level Hib meningitis case fatality ratios (CFRs) were
calculated by adjusting the 11% CFR reported in multicenter
bacterial surveillance sites in Chennai, Vellore, Lucknow,
and New Delhi17 by the state-level proportion of children
without access to medical care. For children with no access
to care, a 100% CFR was assumed.10 State-level estimates
of access to care were based on the NFHS 2006 survey with
care seeking for ALRI considered to be a proxy for meningitis. The median state-level estimate of access to a medical
provider was 71% and ranged from 44%-89% across the
states.12 After adjusting for access to care, the median meningitis CFR was 36% and ranged from 21%-61% across
states.
A proportion of survivors of Hib meningitis suffer
lifelong disabilities. Studies reporting the risk of sequelae
following bacterial meningitis have been conducted in
Chandigargh,20 Kerala,21 Varanasi,22 Hyderabad,23 and
Pune.24 Hib-specific data were presented in 3 of the
studies,20,23,24 but the study in Hyderabad only assessed
hearing deficit and, therefore, was excluded. The pooled
risk of major sequelae following Hib meningitis from the
2 remaining studies in Pune (5 of 13) and Chandigarh
(4 of 13) was 35%.20,24 These proportions are similar to
the proportion of children who suffered sequelae in the
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US and other countries prior to the use of Hib conjugate
vaccines.
Cases of Hib Pneumonia and Deaths
Various studies of clinical pneumonia incidence have been
conducted among children aged less than 5 years at the
community-level in India. In these studies, the incidence
per child per year was reported to be 0.54 (Haryana),25
0.29 (Pune),26 0.86 (Rajasthan),27 0.31 (Delhi),28 0.07
(Maharastra),29 0.10 (Lucknow),30 0.4 (Tripura),31 0.67
(Delhi),32 and 0.53 (Karnataka).33 These studies vary in terms
of geographical location, study design, period of reporting,
and definition of ALRI. We assumed the IQR from all reported estimates to give a plausible national range (ie, 0.290.54 episodes per child per year). This is broadly consistent
with previous estimates for India.34
We assumed that the fraction of ALRI caused by Hib would
be equal to the fraction of ALRI prevented by Hib conjugate
vaccination (3.8%) in the only randomized controlled trial
conducted in Asia (Lombok Island, Indonesia).7 The IQR
of Hib pneumonia incidence was therefore 1102 (3.8% 
29 000) to 2052 (3.8%  54 000) per 100 000 children <5 years
of age. The state-level distribution of Hib pneumonia incidence was assumed to be the same as the state-level distribution for the prevalence of underweight children,12
a consistently reported risk factor for pneumonia in India.35,36 Underweight children have weight-for-age that is 2
or more SDs lower than the median weight-for-age of an international reference population, which includes healthy children from Brazil, Ghana, India, Norway, Oman, and the US.37
Regional estimates of the proportion of mortality of
children <5 years of age caused by pneumonia in children
aged 1-59 months were reported in the Million Death Study:
West (13%); South (8%); East (18%); North (15%); Northeast (16%); and, Central (17%).2 These were multiplied by
total deaths in children <5 years of age in each state to estimate pneumonia deaths in this age group.
The fraction of pneumonia deaths in children aged 1-59
months caused by Hib is a contentious parameter and an important driver of cost-effectiveness results.10 We derived this
fraction by combining: (1) state-level estimates of Hib pneumonia incidence described above; (2) recent multisite estimates of hospitalised pneumonia incidence and CFRs,
extrapolated to parent regions5; and (3) state-level estimates
of access to medical care from the 2005-2006 NFHS survey.12
We further assumed a 23.6% CFR for all severe untreated
pneumonia based on a community-based trial among children 0-4 years in Gadchiroli, central India.38 Using this
approach (Figure 2), we estimated 7% of pneumonia
deaths in children aged 1-59 months to be caused by Hib
nationally, ranging from 1%-11% across states. The 7%
estimate is broadly consistent with the pooled 5%
reduction in radiologic pneumonia found when combining
the results from the only 2 Hib conjugate vaccine
studies conducted in Asia. Using inverse variance metaanalysis, 64% weight was assigned to the randomized
controlled trial in Indonesia (vaccine effectiveness 10%;
Clark et al

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Figure 2. Method for estimating state-level Hib pneumonia cases and deaths at ages 1-59 months.

95% CI 33%, 9%) and 36% weight to the case control study
in Bangladesh (vaccine effectiveness 32%; 95% CI 2%,
54%).39 This pooled estimate is, however, subject to large
heterogeneity (I-squared 82%) and is far lower than
previously reported global estimates. We, therefore,
evaluated a separate scenario assuming Hib to be the cause
of 20% of pneumonia deaths 1-59 months across all states.
The Hib global burden of disease project estimated 21%
globally in children aged 1-23 months based on a global
meta-analysis using studies from Bangladesh, Indonesia,
Chile, and The Gambia.13 This is similar to the fraction
reported by a hospital etiology study conducted in New
Delhi around 20 years ago. In this study, Hib was estimated
to be the cause of 19% (21 of 110) of hospitalized
pneumonia in children <5 years,40 although the study did
not define whether the positive results of latex
agglutination were found in urine (lower validity) or serum
(higher validity). Two other studies from New Delhi and
Chandigarh, estimated Haemophilus influenzae to be the
cause in 16% (20 of 122)41 and 13% (6 of 46)42 of
hospitalized pneumonia cases respectively, but did not
distinguish type b from nontypeable or other Haemophilus
influenzae types.
Cases of Hib NPNM and Deaths
In the multicenter Invasive Bacterial Infections Surveillance
Project (Chennai, Lucknow, Nagpur, New Delhi, Thiruvananthapuram, Vellore) one case of invasive NPNM Hib disease was confirmed for every 5.5 cases of Hib meningitis.43
We applied this ratio to the meningitis incidence rate to
derive an NPNM incidence rate of 4 per 100 000 children
<5 years of age. We assumed 4.3% CFR for those with access

to medical care based on the CFR reported by the Invasive

Bacterial Infections Surveillance Project for Hib-positive
cases without associated meningitis. We doubled the CFR
for children without access to medical care (8.6%), but this
conservative assumption is likely to underestimate the true
mortality burden for invasive NPNM diseases. The adjusted
state-level CFRs ranged from 5%-7%.
Please see Table I for a full summary of the disease burden
parameters used for each state.
Health Care Utilization
For cases of Hib meningitis and Hib NPNM, we assumed that
children with access to medical care would be admitted to
hospital and also have 1 outpatient consultation, either as
a referral or follow-up visit. For all cases of pneumonia, we
assumed 1 outpatient visit per case for those with access to
medical care and that a fraction of these would also be admitted to hospital. Severe clinical hospitalized pneumonia per
100 000 per year in children aged <2 years was recently reported in Chandigarh (2717), Vellore (3075), and Kolkata
(7890). To avoid over-estimation of incidence, we converted
incidence at age <2 years into incidence at age <5 years using
national age distribution assumptions. We then used statelevel estimates of clinical pneumonia incidence at age <5
years and access to medical care to calculate the fraction of
cases with access to medical care who were hospitalized.
We estimated that 3%, 6%, and 13% were hospitalized in
each of the 3 sites. On this basis, we assumed 3% for all North
and North Eastern States, 6% for the South and Western
States, and 13% for the Central and Eastern States. We further assumed that these all-cause pneumonia fractions would
apply to Hib pneumonia, to give median state-level incidence

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Vol. 163, No. 1, Suppl. 1

Table I. Burden-of-disease parameters by state

State

Region

Delhi
Haryana
Himachal Pradesh
Jammu and Kashmir
Punjab
Rajasthan
Chhattisgarh
Madhya Pradesh
Uttar Pradesh
Bihar
Jharkhand
Orissa
West Bengal
North East
Gujaret
Maharashtra
Andhra Pradesh
Karnataka
Kerala
Tamil Nadu

North
North
North
North
North
North
Central
Central
Central
East
East
East
East
North East
West
West
South
South
South
South

Mortality
Incidence per 100 000, 1-59 mo
CFRs 1-59 mo
children
Births <5 yrs per
Life
Percent
Access
Hib
Hib.
Hib
Hib
Hib.
Hib
per 1000
1000
expectancy underweight* to care pneumonia meningitis NPNM pneumonia meningitis NPNM
351
547
125
267
519
1735
629
1981
6216
2487
780
837
1675
281
1203
2258
1619
1165
578
1159

25
64
42
76
52
79
93
94
85
65
72
83
46
46
58
39
55
53
12
43

74
70
73
68
71
69
64
65
66
69
67
66
71
71
71
70
69
70
75
70

26%
40%
37%
26%
25%
40%
47%
60%
42%
56%
57%
41%
39%
36%
25%
37%
33%
38%
23%
30%

89%
88%
69%
73%
87%
66%
67%
53%
76%
72%
71%
76%
70%
44%
64%
74%
60%
71%
89%
77%

1184
1530
1450
1171
1153
1537
1722
2052
1601
1947
1962
1558
1507
1430
1156
1463
1348
1478
1102
1279

22
22
22
22
22
22
22
22
22
22
22
22
22
22
22
22
22
22
22
22

4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4

0.1%
0.1%
0.3%
0.3%
0.1%
0.3%
1.3%
1.7%
1.1%
1.2%
1.2%
1.1%
1.2%
0.5%
0.5%
0.4%
0.6%
0.4%
0.2%
0.3%

21%
22%
39%
35%
22%
41%
41%
53%
32%
36%
37%
32%
38%
61%
43%
34%
46%
37%
21%
31%

5%
5%
6%
5%
5%
6%
6%
6%
5%
6%
6%
5%
6%
7%
6%
5%
6%
6%
5%
5%

*Weight for age < 2SD from WHO reference population.

The North East region includes Sikkim, Arunachal Pradesh, Nagaland, Manipur, Mizoram, Tripura, Meghalaya, and Assam.

of admissions of 55 per 100 000 per year among children aged

<5 years, ranging from 22-185 across states.
Health Service Costs
Costs for outpatient care differed according to whether the
child was taken to a public or private facility, a traditional
healer, or whether only drugs were purchased at a pharmacy.

Costs for inpatient admissions varied with the level and type
of hospital. The NFHS was used to estimate the proportion of
children accessing each type of provider according to State
(Table II).12 The NFHS only includes a primary and
a secondary/tertiary hospital level category for the public
sector. To account for differences in costs between
secondary and tertiary levels, we crudely assumed that

Table II. Distribution of inpatient admissions and outpatient visits by type of provider by state
Inpatient distribution
State

Region

Delhi
Haryana
Himachal Pradeshz
Jammu and Kashmir
Punjab
Rajasthan
Chhattisgarh
Madhya Pradesh
Uttar Pradesh
Bihar
Jharkhand
Orissa
West Bengal
North East,z
Gujaret
Maharashtra
Andhra Pradesh
Karnataka
Kerala
Tamil Nadu

North
North
North
North
North
North
Central
Central
Central
East
East
East
East
North East
West
West
South
South
South
South

Outpatient distribution

Priv hosp Gov hosp Gov hosp Gov hosp Priv

Priv
Priv
Priv
Gov Gov hosp Gov hosp Gov hosp
All
1ary
2ary
3ary
trad* pharm clinic hosp All clinic
1ary
2ary
3ary
61%
83%
39%
18%
72%
32%
43%
46%
23%
86%
62%
18%
22%
14%
67%
56%
67%
70%
63%
41%

0%
0%
38%
62%
0%
49%
16%
23%
64%
7%
0%
59%
31%
61%
9%
9%
0%
18%
0%
17%

37%
16%
21%
19%
26%
18%
39%
29%
12%
6%
36%
22%
44%
24%
23%
32%
32%
12%
35%
40%

2%
1%
1%
1%
1%
1%
2%
2%
1%
0%
2%
1%
2%
1%
1%
2%
2%
1%
2%
2%

0%
3%
2%
1%
0%
2%
0%
12%
2%
6%
3%
12%
16%
19%
0%
4%
0%
4%
11%
4%

1%
3%
6%
19%
5%
7%
6%
4%
7%
18%
11%
6%
6%
19%
4%
3%
0%
0%
0%
1%

67%
75%
51%
31%
73%
41%
66%
55%
80%
61%
74%
31%
62%
29%
51%
62%
40%
38%
4%
25%

13%
15%
14%
8%
16%
14%
7%
12%
2%
11%
6%
8%
3%
3%
28%
17%
40%
38%
50%
28%

12%
0%
5%
3%
0%
6%
12%
4%
1%
3%
3%
4%
3%
10%
4%
0%
0%
3%
7%
0%

0%
0%
14%
28%
0%
22%
2%
6%
6%
1%
0%
27%
4%
14%
4%
3%
0%
10%
0%
12%

8%
3%
8%
9%
6%
8%
6%
8%
1%
1%
4%
10%
6%
6%
9%
10%
19%
6%
27%
28%

0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
1%
0%
0%
0%
1%
1%
0%
1%
1%

1ary, primary; 2ary, secondary; 3ary, tertiary; gov, government; hosp, hospital; pharm, pharmacy; priv, private; trad, traditional.
*Priv Trad refers to private nonmedical healthcare provider (eg, traditional healer).
The North East region includes Sikkim, Arunachal Pradesh, Nagaland, Manipur, Mizoram, Tripura, Meghalaya, and Assam. The following smaller areas were excluded from the evaluation:
Andoman and Nicobar Islands, Chandigarh, Dadra and Nagar Haveli, Daman and Diu, Goa, Lakshadweep, Pondicherry, and Uttaranchal.
zRegional distribution was used because estimates for this state were based on a low sample of children (weighted number of children <25).

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Table III. Average Hib disease treatment costs per inpatient admission and outpatient visit (2010 US$)
Cost per inpatient admission
Type of Hib
disease
Meningitis

Pneumonia/NPNM

Cost per outpatient visit

Region

Priv hosp
All

Gov hosp
1ary

Gov hosp
2ary

Gov hosp
3ary

Priv
trad

Priv
pharm

Priv clinic
or hosp

Gov clinic
or hosp

North
Central
East
Northeast
West
South
North
Central
East
Northeast
West
South

204
345
229
468
483
193
126
213
141
289
298
119

336 (51%)
505 (67%)
217 (24%)
206 (20%)
232 (29%)
201 (18%)
202 (52%)
307 (69%)
129 (25%)
122 (21%)
139 (30%)
119 (19%)

343 (50%)
513 (66%)
225 (23%)
213 (19%)
240 (28%)
208 (17%)
207 (51%)
312 (68%)
134 (24%)
127 (20%)
143 (29%)
124 (18%)

551 (31%)
721 (47%)
433 (12%)
422 (10%)
448 (15%)
417 (9%)
329 (32%)
434 (48%)
256 (13%)
249 (10%)
266 (16%)
246 (9%)

6
1
5
3
0
1
6
1
5
3
0
1

1
1
1
1
1
1
1
1
1
1
1
1

11
9
5
5
6
7
11
9
5
5
6
7

15 (81%)
6 (49%)
13 (77%)
10 (70%)
4 (18%)
5 (37%)
15 (81%)
6 (49%)
13 (77%)
10 (70%)
4 (18%)
5 (37%)

Parentheses show the percentage of total costs by households at government providers.

tertiary-level care accounted for 5% of the reported visits/

admissions in the combined secondary/tertiary category.
Treatment cost estimates are summarized in Table III.
Two published sources were used. Household expenses
were collected from the 60th round of the Government of
India National Sample Survey Organization socioeconomic
survey, conducted in 2004.44 Questions on morbidity and
health care were incorporated in the survey, including
detailed questions about medical expenditures according to
type of disease. Information was collected for every
inpatient admission and outpatient visit for each member
of the sample household during the 365 and 15 days
preceding the survey, respectively. Household expenditures
were categorized according to medicines, user fees, lodging,
transport, etc. Results of the survey on respiratory ailments
in children <5 years old were used for approximating
household costs of pneumonia treatment. For this disease
category, the nationwide sample sizes were 644 outpatient
episodes and 238 inpatient admissions. The cost of
a traditional healer consultation was assumed to be
one-half the cost of a public sector clinic visit.
To estimate household costs of meningitis treatment, the
pneumonia costs were adjusted upwards in accordance
with the additional lengths of stay in hospital as reported
in multicenter surveillance in Lucknow, Chennai, Vellore,
and New Delhi in preparation for the Hib probe study.5
This was 6 days for pneumonia/NPNM and 10 days for meningitis. Opportunity costs, in terms of time spent while looking after a sick child, were included in the sensitivity analysis
by assuming the minimal wage rate of US$3.4 per day,45 multiplied by the average length of stay in hospital. There is no
empirical evidence from India on the costs of treating
a case of sequelae or the life-time earnings lost because of caring for a child with permanent disability, so we did not include sequelae costs in the base case. However, in
a scenario analysis based on a recent sequelae costing study
from Senegal, we assumed undiscounted lifetime costs of
US$53 165 per child with sequel.46 To allow discounting of
future costs, these costs were converted into annual costs
spread over the entire life expectancy of each state.

Government costs of meningitis and pneumonia treatment were derived from a micro-costing study by Krishnan
et al undertaken in the State of Haryana in children aged <5
years.47,48 Data were collected from 2 primary health centers, 6 secondary hospitals, and 2 tertiary hospitals; 6 of
these were government facilities and 2 were private. Another
study on costs of severe pneumonia from 2 non-government organization hospitals in Vellore was used as
a comparator.49
Age Distributions and DALY Estimates
The age distribution of Hib disease also was derived from
the multicenter surveillance study. Among children <2 years
of age with confirmed Hib disease, 24% were aged <3
months, 20% 3-5 months, 21% 6-8 months, 11% 9-11
months, and 23% 12-23 months old.5 We assumed that
6% of children <5 years of age would occur between 24
and 59 months,50 so proportions for <24 months were
adjusted accordingly.
The original DALY formula and disability weights of
0.279 for pneumonia and 0.616 for meningitis were
used.51 Because there are no standard disability weights
available for any of the NPNM diseases, the pneumonia
weight was used. The weighted average disability weight
for meningitis sequelae was 0.34 based on the reported
global distribution of sequelae syndromes52 and their respective disability weights.51 The most common types of single sequela from Hib meningitis are hearing loss and
seizures, comprising 33% and 16% of sequelae cases, respectively. Multiple sequelae are seen in approximately 20% of
sequelae cases.52
Vaccine Coverage and Efficacy
To account for gradual or phased Hib conjugate vaccine introduction, we assumed 50% and 75% of diphtheria-tetanuspertussis (DTP) coverage levels in the first 2 years and full
DTP coverage thereafter. Coverage of the first 3 doses of
DTP were based on the 2009 State-Level Coverage Evaluation
Survey.53 In the base case, we assumed no improvement in
coverage over time, but this assumption was varied in

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Figure 3. State-level coverage of DTP2 vaccination: underweight infants relative to all infants. DTP2 coverage data from
NFHS 2006.

scenario analysis to allow for annual improvements (reductions in the unvaccinated) over the period 2012-2030.
Many children do not receive their vaccines according to
the recommended 6-, 10-, and 14-week schedule. We, therefore, estimated the timeliness of vaccination (age-specific
coverage) for each state using previously described
methods.54
Simple multiplication of vaccine efficacy and vaccine
coverage is likely to overestimate the impact of vaccination because children who receive the vaccine may not be
at the highest risk of mortality. To account for this relative coverage effect, we estimated DTP2 coverage of underweight children relative to the total DTP2 coverage
reported for the cohort,12 the implication being that underweight children are likely to be at higher risk of
death, and that DTP2 would broadly represent the relative coverage for all three doses. Relative coverage multipliers (coverage in underweight children divided by
coverage in the cohort) were calculated for each State
(Figure 3).
To estimate the percent reduction in disease, the base case
estimates accounted for state-level timeliness of vaccination,
dose-specific coverage, and relative coverage. Vaccine efficacy was determined from a recent meta-analysis of controlled clinical Hib conjugate vaccine trials. In this analysis,
efficacy against all forms of invasive Hib disease was 93%
(95% CI 83%, 97%) following 3 doses, 92% (95% CI, 69%,
98%) following 2 doses, and 59% (95% CI 0%, 86%) following 1 dose.55
Herd immunity and waning dose protection were not
considered in the base case, but were included in scenarios.
We assumed that vaccine protection could wane at a fixed
rate of up to 5% per year, and that herd immunity could
increase overall impact by up to 20%.56
Hib Conjugate Vaccine Cost Assumptions
Four Indian companies produce and market Hib conjugate vaccine: Serum Institute of India (Pune), Panacea
S66

Biotec (New Delhi), Bharat Biotech (Hyderabad), and Biological E (Hyderabad). The presentations are monovalent Hib conjugate vaccine and Hib combined with DTP
and hepatitis B vaccines (pentavalent vaccine). Although Indian vaccine procurement is normally processed
between the government and the manufacturers directly,
Global Alliance for Vaccines and Immunization Alliance
funded vaccines are purchased through United Nations
Childrens Fund, which only accepts WHO prequalified
vaccines. The vaccine used in Tamil Nadu and Kerala is
the 10-dose vial pentavalent vaccine produced by Serum
Institute of India procured at a United Nations Childrens
Fund price of US$1.75 per dose.57 For the base case we
assumed a cost of $1.82 per dose (including 4% tax)
and no decline in dose price over time. A declining price
trend was evaluated in scenario analysis.
When estimating the incremental costs of Hib conjugate vaccine, we calculated the cost difference between
a schedule with pentavalent vaccine and with DTP and
hepatitis B vaccines. Phased introduction of monovalent
hepatitis B vaccine in a 10-dose vial started in 2002
with nationwide uptake in 2011. The 2010 prices per
dose of DTP and hepatitis B vaccines were US$0.04 and
US$0.11, respectively.58 Because a 10-dose pentavalent
vaccine vial is used, there is no need to allow for cold
chain expansion.
Uncertainty Analysis
First, we varied each parameter in turn by 10% to establish
the parameters with the greatest influence on the costeffectiveness results (univariate 1-way sensitivity analysis).
Second, we ran 19 alternative scenarios (10 favorable and
nine unfavorable) to evaluate how sensitive the results were
when we changed combinations of influential parameters
(multivariate scenario analysis) (eg, given the uncertainty
around the incidence of Hib disease in India), the most unfavorable scenario assumed a dramatically reduced incidence
rate for both Hib pneumonia (50% of the base value) and Hib
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Table IV. Hib vaccine impact and cost-effectiveness by state: aggregate estimates over the period 2012-2031
Vaccine impact, undiscounted

State
Delhi
Haryana
Himachal Pradesh
Jammu and
Kashmir
Punjab
Rajasthan
Chhattisgarh
Madhya Pradesh
Uttar Pradesh
Bihar
Jharkhand
Orissa
West Bengal
North East*
Gujaret
Maharashtra
Andhra Pradesh
Karnataka
Kerala
Tamil Nadu
India

Region
North
North
North
North
North
North
Central
Central
Central
East
East
East
East
North East
West
West
South
South
South
South

Cost-effectiveness, discounted at 3%

US$ per
US$ per
Meningitis NPNM Total Percent Vaccine Gov cost Family cost Total DALY averted DALY averted
Pneumonia
lives
lives
lives of U5MR costs
savings
savings
DALYs (government
(societal
lives saved
saved
saved saved averted (millions) (millions) (millions) averted perspective) perspective)
278
472
253
262

807
1038
506
662

364
2942
6050
21 415
30 054
19 200
7482
4820
12 577
614
2419
6073
6019
3645
662
2266
127 869

1048
5492
2315
7010
12 112
6431
2493
1995
5468
1170
3793
7993
7979
4636
1403
3490
77 840

34
42
13
19

1119
1552
773
943

0.6%
0.3%
1.0%
0.3%

$36
$43
$10
$20

$0.6
$0.3
$0.3
$0.5

$3.2
$4.9
$1.0
$1.2

34 470
47 096
20 314
25 620

1033
903
500
777

939
800
453
728

41
1453
140
8575
59
8424
152 28 578
364 42 531
179 25 810
68 10 043
60
6876
147 18 191
23
1807
94
6305
233 14 299
188 14 186
127
8408
58
2123
107
5863
2150 207 859

0.4%
0.4%
1.0%
1.1%
0.5%
1.0%
1.2%
0.7%
1.5%
0.9%
0.6%
1.0%
1.0%
0.9%
2.0%
0.8%

$45
$118
$51
$133
$432
$169
$62
$58
$130
$19
$83
$204
$147
$104
$51
$90
$2006

$0.4
$3.0
$2.8
$5.6
$24.6
$2.4
$2.5
$4.7
$8.3
$0.3
$1.1
$4.6
$2.2
$1.7
$1.3
$3.1
$70

$3.7
$9.9
$11.3
$24.4
$82.6
$24.4
$7.8
$4.9
$8.9
$0.4
$7.0
$22.2
$7.7
$7.1
$3.2
$4.4
$240

44 145
220 070
197 709
661 798
1 040 354
617 964
237 934
169 599
439 363
43 599
161 467
374 003
351 765
216 132
64 781
156 945
5 125 128

1017
524
245
192
392
269
252
315
276
420
506
533
411
474
775
555
378

934
479
188
155
312
229
219
286
256
411
463
474
389
441
725
526
331

*The North East region includes Sikkim, Arunachal Pradesh, Nagaland, Manipur, Mizoram, Tripura, Meghalaya, and Assam.

meningitis (32% of the base value) combined with several

other unfavorable assumptions.

Results
Hib Conjugate Vaccine Impact
Between 2012 and 2031, Hib conjugate vaccination is estimated to prevent 207 859 undiscounted child deaths
(
1% of deaths in children <5 years of age) assuming
no benefit from herd immunity. Undiscounted lives
saved were 127 869 for Hib pneumonia, 77 840 for Hib
meningitis, and 2150 for Hib NPNM. The median reduction in total deaths of children <5 years of age was 0.9%
and ranged from 0.3%-2.0% across states (Table IV and
Figure 4).
Hib Conjugate Vaccine Program Costs
The incremental costs of introducing Hib conjugate vaccination would be approximately US$127 million per year based
on current vaccine prices (Table V). Without Hib conjugate
vaccination, the cost of a fully vaccinated child (including
monovalent hepatitis B) is US$2.19. Introduction of Hib
conjugate vaccine increased annual costs four-fold, leading to
costs per fully vaccinated child of US$8.81. The estimated
total incremental cost for 2012-2031 was US$2006 million
after discounting at 3% per year.
Health Care Costs Avoided by Hib Conjugate
Vaccination
Around 15% of the vaccine costs would be offset by health
care cost savings due to reduced cases of Hib disease. This

percentage varied considerably by state; in the Central region

around a one-quarter of the vaccine costs were offset by
health care costs (Table IV). Total costs avoided over the
2012-2031 period would be US$310 million after
discounting at 3% per year. Around 77% (US$240 million)
would be avoided by households, with the remaining
US$70 million by the government.
Hib Conjugate Vaccine Cost-Effectiveness
From a government perspective, state-level cost-effectiveness
ranged from US$192-US$1033 per DALY averted after discounting costs and benefits at 3% per year. With the inclusion of household health care costs, cost-effectiveness
ranged from US$155-US$939 per discounted DALY
averted. The vaccine would be most cost-effective in the
Central and Eastern States (Figure 4). States with the
highest percentage reductions in under-5 deaths were as
diverse as Madhya Pradesh, Jharkhand, West Bengal, and
Kerala.
Uncertainty and Scenario Analyses
For a 10% change in each parameter, in all states the parameter with the largest percent impact on the discounted cost
per DALY averted was relative coverage (12%-17% effect
across states), a parameter rarely included in costeffectiveness studies of vaccines. In all states, the parameter
with the second largest influence was vaccine dose price
(11%-16% effect). The influence and rank of other parameters varied by state, but the incidence of Hib pneumonia
deaths and the efficacy of the vaccine against Hib pneumonia
had important effects (7%-14%) in all states.

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Figure 4. Impact and cost-effectiveness of Hib vaccination by State of India.

A variety of assumptions, favorable and unfavorable to Hib

conjugate vaccine introduction, were considered in scenario
analysis (Figure 5). Costs per DALY averted ranged from
a cost saving scenario, in which health care cost savings
are greater than the cost of the vaccine program itself, to
an unfavorable scenario costing US$1830 per discounted
DALY averted. Figure 5 shows the cost per DALY averted
of the base case scenario (US$331) and the cumulative
effect of introducing favorable and unfavorable
assumptions in sequence. Hence, the most unfavorable

scenario (US$1830) combines all unfavorable assumptions

listed above the base case scenario, and the cost saving
scenario combines all favorable assumptions listed below
the base case scenario.

Discussion
Models of this kind cannot and do not seek to estimate the
precise epidemiologic truth about the impact of a vaccine.
Instead, they provide a framework for exploring the

Table V. Vaccine and syringe costs of the schedule* with and without Hib conjugate vaccine (2010 US$)
Bacille Calmette Guerin
DTP
Hepatitis B
Measles
Polio
Total without Hib vaccine
Costs per child without Hib vaccine
DTP-hepatitis B-Hib vaccine
Total with Hib vaccine
Costs per child with Hib vaccine
Annual incremental cost

Doses in schedule

Costs per dose

Vaccine costs

Injection supply costs

Total

1
3
3
1
4

0.04
0.04
0.11
0.20
0.08

1.82

2 565 849
2 977 936
9 854 186
7 603 174
8 272 044
31 273 189
1.63
143 600 101
162 041 168
8.44
130 767 979

2 137 351
3 594 400
3 594 400
1 467 332
10 793 483
0.56
3 594 400
7 199 083
0.37
3 594 400

4 703 199
6 572 336
13 448 586
9 070 505
8 272 044
42 066 671
2.19
147 194 502
169 240 250
8.81
127 173 579

Price per injection syringe was US$0.06. Price per safety box with capacity of 100 used syringes was US$1.50. Vaccine wastage rates were 61% for Bacille Calmette Guerin, 27% for DTP and
pentavalent vaccine, 33% for hepatitis B vaccine, 35% for measles and 47% for polio.58
*The routine schedule includes booster doses for DTP, polio, and measles at the age of 16-24 mo, but these costs are not included.
4% tax is added to the price per dose.

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+ all household cost savings excluded

1830

+ Hib pneumonia = 50% of base case incidence

1768

+ 5% discount rate

1023

+ Hib meningitis = 32% of base case incidence

687

+ 5% waning protection per year

487

+ outpatient visit costs -10%

470

+ hospitalisation costs - 10%

468

464

+ outpatient visit and hospitalisation rates - 10%

458

+ low efficacy (83% 3 doses, 69% 2 doses, 0% 1 dose)

331

BASE CASE SCENARIO

282

+ 2% price decline/yr
+ high efficacy (97% 3 doses, 97% 2 doses, 86% 1 dose)

252

+ 20% herd effect

193

+ outpatient visit and hospitalisation rates + 10%

187

+ hospitalisation costs + 10%

182

+ outpatient costs +10%

180

+ no relative coverage adjustment

154
71

+ Hib = 20% of pneumonia deaths

29

+ no discounting of costs/benefits
+ household sequelae costs included

1000

2000

3000

4000

5000

US$ per DALY averted

(includes government and household costs avoided)
Figure 5. Scenario analysis showing the cost per DALY averted for the base case scenario and the cumulative effect of
introducing favourable and unfavorable assumptions in sequence. The plus symbol (+) indicates the sequential and cumulative
addition of assumptions to the base case. These are either favorable to the vaccine (bottom half of chart) or unfavorable to the
vaccine (top half of chart).

implications of a range of plausible scenarios or futures,

recognizing that, even with a large body of accumulated
(and forthcoming) clinical evidence, there will be inherent
and unavoidable uncertainties in a population as large and
diverse as Indias.
A large body of local epidemiologic evidence is available
from India for many of the parameters considered in this
model. Where information is lacking or uncertain, we have
had to make assumptions. For example, all-cause pneumonia was used as a proxy when identifying risk-factors for
Hib pneumonia and estimating access to care. Several assumptions also were required to generate plausible estimates
of state-level variation. However, where significant uncertainties exist, we have varied them in scenario analysis to
test the extent to which they have an important bearing on
the results. Our scenario analysis explored the cumulative ef-

fect of adding a series of favourable and unfavorable assumptions in sequence. In our most unfavorable scenario, we
assumed 50% of the base case incidence for Hib pneumonia,
and the unadjusted incidence of 7 per 100 000 <5 years for
Hib meningitis (less than one-third of the base case estimate).
We also applied a 5% discount rate, 10% fewer outpatient
visits and hospitalizations, 10% lower health care costs, lower
vaccine efficacy (83% for 1 dose, 69% for 2 doses, 0% for 1
dose), no herd effect, delayed timing of vaccination, clustering of deaths in the unvaccinated population (relative coverage), 5% waning dose protection per year, and exclusion of
all household health care cost savings. In spite of this extreme
combination of unfavorable assumptions, the cost per DALY
averted remained between 1 and 3  gross domestic product
(GDP) per capita, and would still be considered cost-effective
according to WHO benchmarks.59 Nearly all other scenarios,

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including the base case scenario, are considered highly costeffective with costs/DALY below US$1410, which was the per
capita GDP in India in 2010.60 The WHO thresholds have
been widely debated,61 but the fact that all scenarios, even
those with unfavorable combinations of assumptions, are
within 3 times the GDP per capita, suggest that the vaccine
would be good value for the Indian Government.
A state-level cost-effectiveness analysis of Hib conjugate
vaccination was conducted in the State of Haryana using
an earlier version of our model. With different estimates
and assumptions for their base case scenario,62 the authors
report a discounted cost per DALY averted from a government perspective of US$819, which is similar to our estimate
for Haryana State (US$903).
Investment in Hib conjugate vaccination would increase
annual vaccine costs from US$42 million to US$170 million.
However, current government spending on vaccines is very
low (around 2% of the national health budget)63 and
US$8.81 per vaccinated child is still far less than other countries with similar economies spend on vaccines.64,65 In addition, we estimate that about 15% of the additional vaccine
program costs would potentially be offset by health care
cost savings. Because the Indian health system is dominated
by a large private sector, health care costs are largely in the
form of out-of-pocket costs, which often result in substantial
financial burdens to households. It is estimated that more
than 40% of Indian households have to borrow money or
sell assets to cover hospital expenses.66 In our analysis, the
costs avoided by households accounted for 77% of the total
health care costs avoided.
Our evaluation supports nationwide introduction of Hib
conjugate vaccination. It is encouraging that Hib conjugate
vaccines have already been introduced in Tamil Nadu and
Kerala, but we estimate that these states represent as little
as 4% of the potential lives that could be saved each year in
India. Hib conjugate vaccination would be most costeffective in the Central and Eastern regions where there the
vaccine has the greatest potential to reduce absolute numbers
of deaths. Efforts should therefore be made to expedite
nationwide introduction. The impact of Hib conjugate vaccination in India has already been demonstrated in a limited
setting in India.67 Nonetheless, it will be important to
continue adequate surveillance to monitor the impact of
this vaccine as introduction scales up. n

Author Disclosures
M.S. has received research funding fromGlaxoSmithKline,
Merck, and Pfizer (previously Wyeth Lederle Vaccines)
and has served on the scientific advisory boards of
GlaxoSmithKline, Merck, and Pfizer and received honoraria
for these activities. The other authors declare no conflicts
of interest, real or perceived.
Reprint requests: Andrew D. Clark, MA, Department of Health Services
Research and Policy, London School of Hygiene and Tropical Medicine, 15-17
Tavistock Place, London WC1H 9SH, UK. E-mail: andrew.clark@lshtm.ac.uk.

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