Indian Pediatr 2009;46: 945-954
NTAGI Subcommittee Recommendations
on Haemophilus influenzae Type b (Hib)
Vaccine Introduction in India
Subcommittee on Introduction of Hib Vaccine in
Universal Immunization Program,
National Technical Advisory Group on Immunization,
Correspondence to: Dr Lalit Kant,
Head, Division of ECD, Indian Council of Medical
Research, Ansari Nagar,
New Delhi 110 029, India.
Background: WHO estimates
that Haemophilus influenzae type b (Hib)
caused over 8 million cases of serious disease and
376,000 deaths globally in the year 2000. The
introduction of Hib vaccines has essentially
eliminated Hib disease in countries where they are
routinely used. Now, almost all Hib disease cases
and deaths occur in countries where Hib vaccines
is not incorporated in the routine immunization
Process: The Hib and
Pneumococcal subcommittee of National Technical
Advisory Group on Immunization (NTAGI) in India
met in April 2008. This paper focuses on the
discussions regarding Hib vaccine introduction;
the pneumococcal vaccine discussion is being
published separately. The subcommittee reviewed
the available published and unpublished literature
as well as consulted prominent Hib experts to make
an informed decision regarding the introduction of
Hib vaccine into the routine Universal
Immunization Program (UIP) in India.
Objectives: The meeting was
conducted with the objectives of reviewing the
existing Indian, regional and global data on Hib
disease (meningitis and pneumonia), the data on
safety and immunogenecity of Hib vaccines
manufactured in India, as well as the programmatic
and operational requirements for the introduction
of Hib vaccine in India, with the goal of making a
recommendation on the introduction of Hib vaccine
into the UIP.
committee noted that Hib diseases burden is
suffiently high in India to warrant prevention by
vaccination. Hib vaccines have been demonstrated
to be safe, both globally and in India, and
extremely efficacious in all settings where they
have been used. Hib vaccine fits into the UIP
immunization schedule. Several Indian
manufacturers are currently producing Hib
vaccines, and a detailed analysis showed that
supplier capacity would be sufficient to meet the
present and future demand for India if given
sufficient lead time to increase production.
Recognizing that it is the poorest children that
are most at risk, the Indian Academy of Pediatrics
has already recommended this vaccine for routine
use in India. This subcommittee strongly
recommended that Hib vaccine should immediately be
introduced in India’s UIP.
Key words: H. influenzae, Hib
vaccine, India, Recommendations.
National Technical Advisory Group on Immunization (NTAGI)
appointed a subcommittee to provide recommendations
regarding the introduction of Haemophilus
influenzae type b (Hib) and pneumococcal
vaccines in the Universal Immunisation Program (UIP).
The subcommittee met on April 16-17, 2008 at the
Indian Council of Medical Research, New Delhi. The
purpose of this document is to present the process
and outcome (consensus recommendations) regarding
the introduction of Hib vaccine. The recommendations
of the subcommittee have been submitted to NTAGI. A
document with the summary and recommendations on
pneumococcal vaccine will be submitted separately
for publication. The list of participants who
attended the meeting is in Appendix 1.
India’s Multi Year Plan (2005-10)
for immuni-zation(1) addresses the need for
"accelerated introduction of new and underutilized
vaccines against diseases with significant morbidity
and mortality in India". Four criteria are outlined
for the introduction of new vaccines into the UIP: (i)
the disease burden should be judged to be sufficient
to warrant the introduction; (ii) the vaccine
should be safe and effective; (iii) the cost
of the vaccine should be reasonable and suitable for
absorption into budget provision even if the
introduction is funded, and; (iv) financial
sustainability should be built into the plan of new
vaccine introduction. Against this background, the
subcommittee set the following objectives for the
discussion regarding Hib vaccines:
• Review the available data on
Indian, regional and global burden of Hib disease
to assess the need for Hib vaccine introduction in
UIP. The list of documents reviewed is given in
• If consensus is to recommend
its introduction, to define appropriate options
including operational strategies for introduction
of Hib vaccine in UIP.
• To identify needs for
additional research including evaluation of the
impact of Hib vaccine introduction.
Epidemiology of Hib Disease
Global Burden of Disease
The WHO estimates that globally
Hib caused over 8 million cases of serious disease
and 376,000 deaths in the year 2000. (WHO; In
press). Pneumonia and meningitis comprise the
majority of the severe diseases caused by Hib in
developing countries. Meningitis is the most severe
form of Hib disease, with case fatality rates
ranging from 20-25% and rates of severe neurologic
sequelae in survivors of 30-40%. Rates of Hib
pneumonia in developing countries have been
estimated to be 2-5 times higher than rates of Hib
meningitis. Countries using Hib vaccine in national
immunization programs have virtually eliminated Hib
disease; however, Hib disease continues to occur in
countries that do not use Hib vaccines widely(2).
Recent studies assessing the
difference in disease incidence between vaccinated
and unvaccinated groups (called "probe studies")
have demonstrated a high burden of Hib disease in
South and Southeast Asia. For example, a Hib vaccine
probe study in Indonesia showed that the rate of
bacterial meningitis prevented by Hib vaccine was 67
per 100,000 children <2 years of age(3).
Surveillance studies in South Asia have shown high
burden of Hib meningitis(3). In Pakistan, of 237
children with probable bacterial meningitis, Hib was
detected in the CSF of 45 children (18.9%). In this
study, the minimum detected incidence rate of Hib
meningitis in the metropolitan region of Hyderabad
and its surrounding population was 7.6 per 100,000
(95% CI: 4.29, 12.59) in children <5 years of age
and 38.1 (95% CI: 22.35, 61.4) per 100,000 in
children <1 year of age(4). In Sri Lanka, a
surveillance study done in 2004 showed that the rate
of Hib meningitis was 20.1 (95% CI: 14.5, 27.8)
cases per 100,000 children <5 years(5).
Hib Disease in India
Hib disease has been shown to be
a significant cause of morbidity and mortality in
Indian children <5 years of age, particularly those
in the poorest communities. Hospital-based studies
in India have shown that Hib and pneumococcus were
the most common causes of childhood bacterial
meningitis; however, these types of studies do not
provide population based disease incidence(6,7,8). A
multi-centre study from Jaipur, Jodhpur, Delhi and
Kolkata found that 0.5-2.6% of all hospital
admissions were attributable to bacterial
meningitis, including Hib(9). Studies that tested
cerebrospinal fluid (CSF) using other sensitive
laboratory techniques such as latex agglutination
testing (LAT) or counterimmune electrophoresis (CIE)
along with culture found that 25% (range: 14-35%) of
bacterial meningitis was attributable to Hib
in India (Table I)(10-14).
Proportion of Meningitis Caused by Hib
% Hib positive
Deivanayagam, et al. 1993(11)
||2 mo - 11 y
Singhi, et al. 2002(13)
||1 mo - 12 y
Suvarna Devi, et al. 1982(14)
Mani, et al. 2007(12)
Chinchankar, et al. 2002(10)
||1 mo - 5 y
Studies using culture, latex agglutination,
counter immunoelectrophoresis and/or PCR.
Indian studies have reported case
fatality rates of Hib meningitis of 20-29%(8-10,15),
while all invasive Hib disease (including
meningitis) had a case fatality rate of 16%(8). In
addition, neurological sequelae are common among
children who survive Hib meningitis. Researchers in
Pune followed 14 Hib meningitis cases and found that
5 (36%) survivors had at least one neurological
sequelae, including persistent seizures (18%),
isolated hearing loss (27%), and moderate to severe
developmental delay (9%)(10). A recent study in
Chandigarh demonstrated that 40% of children with
acute bacterial meningitis had sequelae at 12 months
of follow-up(16), Another study in Kottayam found
that 23% of the children surviving acute bacterial
meningitis after treatment had developmental delay
and 20% had mental retardation(17).
A review of available data showed
that Hib is also a leading cause of pneumonia in
India. Indian studies of the etiology of pneumonia
using some non-specific methodologies such as
nasopharyngeal (NP) swab collection in addition to
lung fluid taps – tested using a combination of
sensitive techniques (LAT, CIE, and/or polymerase
chain reaction (PCR)) in addition to culture found
Hib to be responsible for between and 13-19% of
pneumonia and lower lung disease (Table II)(18-20).
Proportion of Acute Lower Respiratory Infections Caused by Hib
% Hib positive
Bahl, et al. 1995(18)
||Severe and very severe pneumonia
Kumar, et al. 1984(19)
||Lobar pneumonia and empyema thoracis
Patwari, et al. 1996(20)
||Pneumonia and bronchopneumonia
Studies using culture with latex agglutination, counter immunoelectrophoresis and/or PCR.
Based on a systematic analysis of
local and regional data that met specified quality
parameters, a mathematical model devised by the
World Health Organization and vetted by experts
estimated the burden of Hib disease in India in the
year 2000 to be about 2.4 million cases and 72,000
deaths in children <5 years of age, accounting for
approximately 4% of all child deaths in India (WHO;
Hib carriage among infants was
found to be common in India (Table III),
with an estimated prevalence of 7.2% (range
6.8-16.3%)(21,22), which is consistent with regional
data. Studies have shown carriage prevalence of 4-7%
in Turkey, Thailand, and Vietnam(23-25).
Prevalence of Nasopharyngeal Carriage Among Healthy Children in India
Das, et al. 2002(15)
||Chandigarh, Kolkata, Vellore
Sekhar, et al. 2008(21)
*projected based on a subset of Hi typed as Hib
Hib carriage rates increase
throughout infancy and into the second year of life,
peaking at age 18-21 months at a prevalence of
20.3%(21). The likelihood of carriage has
been shown to increase if the child’s parents were
illiterate, if they lived in a katcha (mud/thatch)
house, or if they lived in crowded conditions(21).
Antibiotic resistant strains of
Hib are common across India, and resistance to all
major antibiotics used in India has been described.
Reports of prevalence of resistance of Hib to
ampicillin range from 15.0% to 60.4%(6,26-28).
Similarly, rates of resistance against several other
antibiotics, including third generation
cephalosporins, chloramphenicol, cotri-moxazole and
erythromycin, ranged from 3% to 67%(6,7,15,26-28).
Globally, millions of doses of
Hib vaccine have been administered in the last 2
decades, and have been found to be extremely safe.
Studies, both published and unpublished, that have
been done on Indian Hib vaccines were presented at
the meeting. One study reported rates of solicited
general symptoms (fever, irritability, drowsiness,
loss of appetite) following inoculations of
0.8%(29). Other studies reported that there were no
significant adverse reactions associated with Hib
Efficacy and Immunogenicity
Hib vaccine has been shown to be
>95% efficacious in diverse populations around the
world. The efficacy of Hib vaccines was demonstrated
in numerous clinical trials in Europe, the US, and
The Gambia. In the mid 1990’s, a large vaccine trial
was conducted in The Gambia, comparing Hib vaccine
mixed with diphtheria-tetanus-pertussis (DTP) to DTP
alone. This trial showed a protective efficacy of
95% (95% CI: 67-100%) against all invasive Hib
disease after three doses(33). Experts agree that it
is no longer ethical to conduct randomized clinical
trials to demonstrate the clinical efficacy of Hib
vaccine, since this has been demonstrated in a wide
variety of settings; based on available
immuno-genicity data there is no reason to suspect
that efficacy will be any different in India.
Hib vaccine has nearly eliminated
Hib disease in all developed and developing
countries where it has been introduced(2).
Recent studies in Kenya and Uganda showed dramatic
reductions in Hib disease rates after Hib vaccine
was introduced into each country’s routine
immunization program(34,35). One example from South
Asia is a case-control study in Bangladesh which
showed that 3 doses of Hib conjugate vaccine reduced
rates of laboratory confirmed meningitis by 90% and
radiologically confirmed pneumonia by 16-32%(36).
Numerous immunogenicity studies
have been performed in India, and have shown that
all of the vaccines tested are highly immunogenic.
Sero-conversion after vaccination, as defined by
antibody concentration of >0.15 µg(37), was 100% in
all Indian studies(30-32). Furthermore, combination
vaccines have proven highly immunogenic. Both DTwP/HepB/Hib
combination vaccine(29) and Hib vaccine combined
with locally produced DTwP(31) proved as immunogenic
as single antigen Hib vaccines.
Hib vaccines have been shown to
induce significant "herd effect" in both developed
and developing country settings; that is, immunizing
a proportion of the population reduces disease in
unimmunized children living in the same community.
Several studies have shown a substantial herd effect
with the introduction of Hib vaccine(38-41). In
Gambia, Hib vaccine was introduced in the mid-1990s,
but vaccine supply was interrupted at times and
coverage with 3 doses of vaccine ranged from 62% to
75%. Nevertheless, carriage rates in unvaccinated
children fell from 7.7% to 3.8%, and invasive Hib
disease has virtually disappeared(42,43). Therefore,
a population does not have to be fully vaccinated in
order for substantial benefit to be seen.
Both Indian and international
expert committees have recommended the use of Hib
vaccines. WHO issued a position statement that all
countries should introduce Hib vaccine, and that
"the lack of local surveillance data should not
delay the introduction of the vaccine especially in
countries where regional evidence indicates a high
burden of disease"(44). The Indian Academy of
Paediatrics also issued a statement in 2004 that "Hib
vaccine should be offered to all children"(45).
Vaccine Supply and Presentation
Hib vaccines are available in
several formulations: monovalent, tetravalent (DTwP-Hib),
pentavalent (DTwP-HepB/Hib), and in similar
combinations with acellular pertussis vaccine. At
the time of the meeting, three pentavalent, 2
tetravalent and 4 monovalent Hib vaccines from
Indian manufacturers were licensed in the country,
and an additional 6 pentavalent and 3 monovalent
vaccines were in development. Two Indian pentavalent
vaccines (liquid) in addition to 2 imported vaccines
(1 liquid, 1 lyophilized) had been prequalified by
the WHO and are available through UNICEF
procurement. A third Indian lyophilized formulation
is expected to be prequalified in the next year. The
vaccines are available in a variety of vial sizes.
Prequalified pentavalent vaccines are available in
single, two and ten-dose presentations.
Indian manufacturers currently
produce 4 million doses of Hib-containing vaccines
each year for the private market, although installed
capacity (ability to produce given sufficient lead
time) is significantly higher at an estimated 70
million doses per year. Pentavalent vaccine supply
offered to GAVI-eligible countries from two
multi-national suppliers is currently 66 million
doses per year; potential capacity is significantly
higher. Supplier capacity would be sufficient to
meet the present and future demand for India if
given sufficient lead time to increase production.
Hib vaccination fits into the UIP
immunization schedule. The earliest age when
vaccination can be given is 6 weeks, with a minimum
gap of 4 weeks between each dose. The recommended
ages for vaccination (6, 10, and 14 weeks) which
corresponds with the UIP schedule for oral polio,
DwPT and hepatitis B vaccines.
Hib vaccines have been
demonstrated to be highly cost-effective. A recent
study in Kenya showed that the cost per discounted
death averted was US $1,197(46), and a study from
Indonesia concluded that the cost per death and per
discounted Disability Adjusted Life Year (DALY)
averted was US$ 3,102 and US $74, respectively(47).
In the Indonesian analysis, it was estimated that
Hib vaccine would prevent 4.9% of the current
A preliminary cost-effectiveness
analysis from India, using the WHO disease burden
estimates for India, suggests that Hib vaccine
introduction into the UIP is highly cost-effective.
This analysis indicates that, with conservative
burden of disease assumptions and the 2008 UNICEF
price of US $3.60 per Hib vaccine dose, the costs
per DALY averted is US $254 (Ms Ulla Griffiths,
personal communication, 2008). Based on trends of
other vaccines in national programmes, prices would
be expected to decline significantly from current
levels. With a price of US $2.00 per dose of
pentavalent vaccine, the cost per DALY averted will
be US $26. In 2007, the GDP per capita in India was
US $785. Hence, the costs per DALY averted from Hib
vaccine is estimated to be considerably less than
the GDP per capita and according to WHO benchmarks,
the vaccine is therefore considered "highly
The committee also considered
programmatic issues in the context of adding new
vaccines to the UIP, including logistic issues such
as training, vaccine supply, cold chain capacity,
and financing. The committee considered country-wide
vs. phased introduction. The committee also
considered that 11 states had already introduced or
were soon to introduce Hepatitis B vaccine as part
of Phase II of Hepatitis B vaccine introduction
plan. Since pentavalent vaccine contains Hepatitis
B, the committee considered this to be an
opportunity to harmonize the introduction of Hib
with Hepatitis B vaccine. Although a detailed
assessment of vaccine-associated adverse event
surveillance, disease surveillance, and UIP capacity
were beyond the scope of this meeting, it was
pointed out that such issues need to be considered
simultaneously with new vaccine introduction. The
committee also felt that the introduction of this
vaccine even in low-performing states with <60% DTP
vaccine coverage will have substantial impact on
reducing Hib disease burden because of the herd
immunity induced by the vaccine.
Based on the above
considerations, the committee came to the following
conclusions and recommendations regarding
introduction of Hib vaccine in India:
1. There is sufficient evidence
of relatively high Hib disease burden in India to
warrant the early introduction of Hib (conjugate)
vaccine into the UIP with a goal of national
coverage by 2012.
2. As simultaneous nationwide
roll-out will be logistically challenging, Hib
should be introduced in a phased manner beginning
as soon as possible.
3. The pentavalent vaccine
should be introduced initially in at least the 11
states that are currently part of Phase II of
Hepatitis B vaccine introduction. In addition,
states with high under-5 mortality such as Uttar
Pradesh and Bihar should be considered for
introduction of the pentavalent vaccine as soon as
possible, at least in some districts as part of
the first phase of introduction in those states.
Even though these states have relatively poor
immunization coverage, the introduction of this
vaccine is likely to protect large number of
children both by the direct effect on immunized
children and by the "herd effect" on those who are
4. The preferred formulation is
the liquid pentavalent since it will eliminate the
need for administering an additional injection,
simplify the delivery of vaccine in the field, and
reduce the training requirements and supplies.
Vial size should be determined by programmatic
considerations such as cold chain and projected
5. To monitor trends in disease
and carriage reduction, and to evaluate the
potential future need for a booster dose (as
evidenced by disease occurrence in older age
groups), it is critical to establish ongoing
surveillance for invasive bacterial diseases prior
to and post vaccine introduction.
6. Research activities should
be coordinated by the Indian Council of Medical
Research (ICMR) in collaboration with other
agencies such as Department of Biotechnology (DBT).
A coordination plan should be developed within 6
months. A research subcommittee should be formed
to oversee the scientific issues involved with
7 There should be an assessment
of joint introduction of pneumococcal and Hib
vaccines in a high mortality area to assess impact
of these vaccines on mortality reduction, as both
are effective against bacterial meningitis and
pneumonia, two conditions with high case-fatality.
8. The committee recommends
strengthening the system for disease surveillance,
vaccine safety monitoring and program monitoring
within UIP, which will coordinate with the
9. To optimize the success of
Hib vaccine introduction, the committee
recommended that sufficient resources (personnel,
material and design) be put into the UIP system to
ensure a transformational change, not merely an
incremental change. A separate mechanism
(including a dedicated committee) should be formed
to review and define the needed human resources at
the central, state, district, and local levels for
optimal UIP performance.
Hib vaccine has the potential to
prevent over 70,000 child deaths and significantly
more cases of illness and disability every year in
India. Children of families who could afford the
vaccine have been receiving it for several years in
private medical care setting. Recognizing that it is
the poorest children that are most at risk of
disease, as well as vulnerable to serious adverse
consequences, the Indian Academy of Pediatrics and
the WHO have recommended that all children be
offered the vaccine.
Subsequent to the presentation of
these recommendations, NTAGI in its July 2008
meeting not only endorsed them but also resolved to
recommend to the Government of India that Hib
vaccine should be introduced in all states as early
as feasible. Although implementation will be a
challenge given the strains on the current system,
the government officials have made a commitment to
put the resources into the system necessary to make
Hib vaccine available to all Indian children as
quickly as possible. The case for adoption of Hib
vaccine in the UIP is clear; to help India make
progress towards combating a large but preventable
burden of disease and reducing antibiotic resistance
that increases healthcare cost and health risk for
children who may get Hib disease. Indian suppliers
now contribute to meeting global demand for the
vaccine and the additional supply and competition
should help contribute to the trend of making Hib
vaccine less expensive than at present. It is now
time to begin adopting the vaccine in UIP. To help
move the adoption of vaccine closer to reality, the
GAVI Alliance has offered the opportunity to apply
for funding to help adopt new vaccines and to
strengthen the immunization system. The government’s
commitment to the health of all children in India is
an integral part and important step in reaching
India’s health goals and addressing issues of
inequity as it prevails now.
Funding: Indian Council of
Medical Research (ICMR) with part funding from
Competing interests: None
Appendix 1 List of
JP Muliyil, CMC Vellore - Chairperson; MK Bhan,
Secretary, DBT; SK Bhattacharya, Additional
DG-ICMR; Lalit Kant, Head, ECD, ICMR; NK Arora,
Executive Director, INCLEN Trust; M Santosham,
Johns Hopkins University; Thomas Cherian, WHO
HQ, Geneva; Ashok Dutta, New Delhi; Jacob
John, Vellore – Co-Chair NTAGI; Hamid Jafari,
National Polio Surveillance Unit; Naveen
Thacker, Indian Academy of Pediatircs
representative; Padmanaban, Tamil Nadu Health
Services; M Senthilmazhan, Saradha Suresh and
Ambujam Nair Kapoor, ICMR.
Andrew Clark, London School of Hygiene and
Tropical Medicine; Rana Hajjeh, Hib
Initiative; Anuradha Bose, Christian Medical
College, Vellore; Rajesh Kumar, PGIMER,
Chandigarh; Meredith Shirey, UNICEF; Lois
Prevor Drumm, Johns Hopkins University; Aruna
Chandran, Johns Hopkins University, and SD
Khaparde, DC Immunization, MOHFW.
Sanjeev Upadhaya, USAID; Krishna Rao, Public
Health Foundation of India; Syed Abbas, Public
Health Foundation of India; R K Agarwal,
President, Indian Academy of Pediatircs; Ajay
Gambhir, Indian Medical Association; Soren
Spanner, UNICEF; Satish Gupta, UNICEF; Sunil
Bahl, NPSU; Rajeev Gera, NPSU; Pem Numgyal,
WHO SEARO; Paul Francis, WHO India;
Chandrakant Lahariya, NPSU; Shamila Sharma,
NPSU; Harish Kumar, UNICEF, and Tim Peterson,
Appendix 2 Data Reviewed During Subcommittee Process
burden and Epidemiology
Batuwanthudawe unpublished(5), Cherian
Gessner 2008(47), John 1998(6), Zaidi in
Das 2002(15), ICMR 2008(22), Oguzkaya-Artan
2007(23), Olsen 2005
(24), Sekhar 2008(21), Tran 1998(25)
Bahl 1995(18), Kumar 1984(19), Patwari
1996(20), Puri 1999(24)
Chinchankar 1998(10), Deivanayagam 1993(11),
IBIS 2002(8), ICMR
2008(22), Kabra 199(19), Mani 2007(12), Singhi
|Chinchankar 1998(10), Singhi
|Chinchankar 1998(10), IBIS
2002(8), Kabra 1991(9), Steinhoff 1998(7)
Antibiotic use and
Das 2002(15) , Jain 2005(27), John 1998(6),
Mani 2007(12), Puri
1999(26), Singhi 2002(13), Steinhoff 1998(7)
efficacy, and impact
Acharya 1997(32), Adegbola
1998(42), Adegbola 2005(43), Baqui 2007(36),
Bavdekar 2007(30), Cherian 2002(31), Cowgill
2006(34), Gallo 2002(38), Gessner 2005(3),
Jain 1997(27), Kayhty 1983(37), Kumar
1997(29), Lee 2008(35), Makela 2003(40),
Moulton 2000(41), Mulholland 1997(33), Perdue
2000(39), Watt 2003(2)
|Akumu 2007(46), Gessner
2008(47), Griffiths (personal communication)
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