Hib Vaccines: What is new ??
A Review
Dr S G Kasi
Bengaluru
• Improved Hib vaccines
• New Hib Combos & combos containing
DTaP+IPV+Hib combined with other infant
vaccines
• Effectiveness data on Hib vaccines
• Cost-effectiveness data on Hib vaccines
• Changes in Hib epidemiology following use of
Hib vaccines
IMPROVED HIB VACCINES :
Improved Hib vaccines…
• Experimental design to optimize an Haemophilus influenzae
type b conjugate vaccine made with hydrazide-derivatized
tetanus toxoid . Glycoconjugate Journal Volume 28, Number 7,
463-472
• There is a need for a simple and high-yielding manufacturing
process. To improve the yield and rate of the reductive
amination conjugation reaction used to make this vaccine,
some of the carboxyl groups of the carrier protein, tetanus
toxoid, were modified to hydrazides, which are more reactive
than the ε -amine of lysine. Other reaction parameters,
including the ratio of the reactants, the size of the
polysaccharide, the temperature and the salt concentration,
were also investigated.
Improved Hib vaccines…
• Improved immune responses in mice using the novel
chitosan adjuvant ViscoGel, with a Haemophilus influenzae
type b glycoconjugate vaccine. Vaccine
Volume 29, Issue 48, 8 November 2011, Pages 8965-8973
• Mixing Act-HIB with ViscoGel, induced significantly enhanced
IgG1 and IgG2a titers in serum (p < 0.05).
• The antigen dose could be reduced ten-fold in combination
with ViscoGel and the antibody titers observed were similar to
10 μg Act-HIB administered alone
• The Act-HIB specific cellular response was stronger in mice
vaccinated together with ViscoGel (p < 0.05).
NEW COMBOS WITH HIB &
COMBOS CONTAINING
DTAP+IPV+HIB COMBINED WITH
OTHER INFANT VACCINES
Made in INDIA v/s the “Foreign brand”
• A phase III randomized, controlled study to assess and
compare the immunogenicity and tolerability of single and
multi-dose vials of DTwP-Hib, a fully liquid quadravalent
vaccine and their comparison with TETRAct-Hib vaccine in
Indian infants aged 6–14 weeks. Vaccine Vol 29, 48, 8 Nov 2011, 8773-79
• Postvaccination, geometric mean titres for each component
did not differ significantly between the single dose vial and
multi dose vial subgroups and among the two study groups
• Adverse events observed were within the range quoted in
literature
• Immunogenicity and safety of an indigenously manufactured
reconstituted pentavalent (DTwP-HBV+Hib) vaccine in
comparison with a foreign competitor following primary and
booster immunization in Indian children Vaccine Vol 7, 4 2011,451 – 57
• Post-primary immunization, 100% seroprotection was noted for
Diphtheria, Tetanus, Hepatitis B and PRP-Hib components in both the
vaccine groups
• For pertussis, response was 96.1% in SIIL and 95.4% in GSK group.
• The overall safety profile as well as persistence of antibodies against all
vaccine components up to the time of booster immunization was
comparable between the SIIL and GSK groups.
• A marked rise of all antibody concentrations indicated effective priming
• The booster dose was safe, well tolerated with a significant increase in
antibody concentrations of all the vaccine antigens in both the groups.
• One-year post-primary antibody persistence and booster
immune response to a DTaP-IPV//PRP~T vaccine (Pentaxim)
given at 18 - 19 months of age in South African children
primed at 6, 10 and 14 weeks of age with the same vaccine.
S Afr Med J 2011;101:879-883.
• A DTaP-IPV//PRP~T vaccine,was given to 182 healthy children in South
Africa at 18 - 19 months of age following priming with the same vaccine
plus a monovalent HBV at 6, 10 and 14 weeks of age.
• One month after primary vaccination, at least 94.3% of participants were
seroprotected against tetanus , diphtheria , poliovirus and Hib infection .
• Before the booster dose, the SP rates ranged from 65.7% to 100%.
• One month after the booster dose, SP rates were 97.7% for Hib , 100.0%
for diphtheria and 100% for tetanus and poliovirus types 1, 2, 3.
• At least 95.7% of participants had fourfold post-booster increases in antipertussis antibody titres
• The DTaP-IPV//PRP~T vaccine booster was well tolerated, with fever
≥39.0°C in only 1.7% of participants
DTwP+IPV+HBV/Hib
• A randomized, dose-ranging assessment of the
immunogenicity and safety of a booster dose of a combined
diphtheria-tetanus-whole cell pertussis-hepatitis Binactivated poliovirus-Haemophilus influenzae type b (DTPwHBV-IPV/Hib) vaccine versus co-administration of DTPwHBV/Hib and IPV vaccines in 12 to 24 month old Filipino
toddlers
• Human Vaccines. Volume 8, Issue 3 March 2012
DTwP+IPV+HBV/Hib
• Three formulations of a combined, candidate hexavalent
diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated
poliovirus-Haemophilus influenzae type b conjugate vaccine
(DTPw-HBV-IPV/Hib, GlaxoSmithKline Biologicals) differing
only in IPV antigen content (full-dose, half-dose and one-third
dose as compared to available stand-alone IPV vaccines), were
evaluated when administered to healthy toddlers. Controls
received separately administered licensed DTPw-HBV/Hib and
IPV vaccines.
• Three hundred and twelve Filipino children were vaccinated in
their second year of life.
DTwP+IPV+HBV/Hib
• Each DTPw-HBV-IPV/Hib formulation was non-inferior to
control in terms of pre-defined criteria for IPV
immunogenicity. Post-vaccination GMTs against each
poliovirus type were increased between 4.2 and 37.9-fold
over pre-vaccination titers
• Non-inferiority to other vaccine antigens was also
demonstrated
• The safety profile of the 3 DTPw-HBV-IPV/Hib formulations
resembled licensed DTPw-HBV/Hib and IPV in terms of the
frequency and intensity of adverse reactions after vaccination.
• Further investigation of DTPw-HBV-IPV/Hib containing
reduced quantity of IPV antigen for primary vaccination in
infants is warranted
Co administration with Hep A
vaccine
• Immunogenicity and safety of an inactivated hepatitis A
vaccine when coadministered with Diphtheria-tetanusacellular pertussis and haemophilus influenzae type B
vaccines in children 15 months of age. Pediatr Infect Dis J.
2011 Sep;30(9):e164-9.
• Coadministration of the 3 vaccines did not impact
immunogenicity of the HAV, DTaP, or Hib vaccines. Vaccines
were well tolerated in all groups
• Immunogenicity and Safety of an Investigational Fully Liquid
Hexavalent Combination Vaccine Versus Licensed
Combination Vaccines at 6, 10, and 14 Weeks of Age in
Healthy South African Infants. Vaccine April 2011 - Volume 30
- Issue 4 - pp e68-e74
• Conclusions: The new, fully liquid, investigational hexavalent
vaccine in the Expanded Program on Immunization schedule,
with/without hepatitis B at birth, is highly immunogenic and
safe compared with control vaccines, warranting further
development
•
HibMenCY
• Immunogenicity and Safety of H influenza Type b N
meningitidis C/Y Conjugate Vaccine in Infants .
Pediatrics. 2011 2011;127;e1375 .Originally published online May 29,
• The HibMenCY was immunogenic against MenC and MenY
and induced anti–polyribosylribitol phosphate antibody levels
noninferior to those of licensed Hib conjugate vaccine. The
safety profile of the HibMenCY was clinically acceptable and
comparable to Hib conjugate vaccine.
Hib CV in Adults with immunodeficiency
• 32 patients with CRF and 19 controls were immunized with
one dose of pediatric Hib vaccine
• Serum antibody levels were assessed pre- and 1, 6, 9 months
post-vaccine
• Functional antibody activity was studied using a serum
bactericidal assay.
• 4 week post-vaccination, 97% developed protective antibody
with a 14-fold increase in Ab titers
• In 91%, the antibody exhibited bactericidal activity
• In the majority of patients, protective antibody persisted 9
months post-vaccine.
• The pediatric Hib vaccine is highly
immunogenic in this group, with higher
response compared to other vaccines
administered to such patients (hepatitis B and
pneumococcal vaccines)
EFFECTIVENESS DATA ON HIB
VACCINES
• Effectiveness of Haemophilus Influenzae Type B Conjugate
Vaccine for Prevention of Meningitis in Senegal.
Pediatric Infectious Disease Journal: May 2011 Vol 30 Issue 5 - pp 430-32
• The adjusted vaccine effectiveness for ≥2 doses was 95.8%
(95% confidence interval, 67.9%–99.4%).
• Hib vaccine appears to be highly effective in preventing Hib
meningitis in Senegal
Chile & Columbia: No Booster , Uruguay & Argentina : With Booster
COST-EFFECTIVENESS DATA ON HIB
VACCINES
• A decision analytic model was used to estimate morbidity and
mortality from Hib meningitis, Hib pneumonia and other
types of Hib disease with and without the vaccine.
• Estimated costs per discounted DALY averted are US$ 9,323 in
Belarus and US$ 267 in Uzbekistan.
• The primary reason why the cost-effectiveness values are
more favourable in Uzbekistan than in Belarus is that
relatively more deaths are averted in Uzbekistan due to higher
baseline mortality burden. Two other explanations are that
the vaccine price is lower in Uzbekistan and that Uzbekistan
uses a three dose schedule compared to four doses in
Belarus.
• COST EFFECTIVENESS STUDY OF HIB VACCINATION FOR
CHILDREN BELOW 5 YEARS IN JORDAN
Issam al- Khawaja,MD, JMF
• Effectiveness of Haemophilus influenzae Type b Conjugate
Vaccine Introduction Into Routine Childhood Immunization in
Kenya. KD Cowgill, M Ndiritu, J Nyiro, et. al.
The effectiveness of the vaccine was 88%, similar to other
countries, both developing and developed.
• Economic evaluation of Haemophilus influenzae type B
vaccination in Indonesia: a cost-effectiveness analysis. Journal
of Public Health | Vol. 29, No. 4, pp. 441–448
CHANGES IN HIB EPIDEMIOLOGY
FOLLOWING USE OF HIB VACCINES
CURRENT EPIDEMIOLOGY AND
TRENDS IN INVASIVE
HAEMOPHILUS INFLUENZAE
DISEASE—UNITED STATES,
1989–2008 .
CLIN INFECT DIS. (2011) 53 (12): 1230-1236
Changes in Hib epidemiology 1
• Between 1989 to 2008, for
the general US popln, 65%
drop from 4.39 to
1.55/100,000 people
• For children < 5 years, , a
95% reduction from 37.18/
100,000 children in 1989 to
3.09/100,000 children
• 1989: Mean age- 28y, 32%<
5y
• 2008: Mean age- 63y, 48% >
65y
Changes in Hib epidemiology 2
•
Large increases in the incidence
of infection caused by non-b
types and nontypeable strains
were observed
• The largest increase in incidence
was observed for serotype f (0.06
cases per 100 000 population in
1989 to 0.25 cases per 100 000
population in 2008; 317%
increase)
• Serotype f was observed
primarily among adults, with 83%
of cases reported in adults aged
18 years.
Changes in Hib epidemiology in
young children
• 632/4838(13%) in <5yrs
• 401/632 (63.5%) in <1yr
• 175/632 (27.7%) in <1 month
• Invasive Haemophilus influenzae in British Columbia: nonHib and non-typeable strains causing disease in children and
adults. International Journal of Infectious Diseases
Volume 15, Issue 3, March 2011, Pages e167-e173
• 98 isolates in 2008-09
• 66% were caused by non-typeable strains, followed by
serotypes b (12%), a (10%), f (10%), and e (1%).
• Serotypes b and f and non-typeable strains caused disease
mainly in adults over 18 years of age
• Serotype a caused disease mainly in children under the age of
2 years
• 31% identified as genotypic β-lactamase-negative ampicillinresistant (BLNAR) strains
• Invasive disease due to Haemophilus influenzae serotype b
ten years after routine vaccination, South Africa, 2003–2009.
Vaccine .2011.11.066
• S A started routine infant immunization against Hib vaccine in
1999 with an accelerated three-dose schedule of Hib
conjugate vaccine (HibCV) without a booster dose
• After an initial rapid, marked decline, detection rates of Hib
disease in children <5 years increased from 0.7 per 100,000
population in 2003 to 1.3/100,000 in 2009 (p < 0.001).
• 51% were classified as vaccine failures
• 53% were not HIV infected
• Of vaccine failures, 55% occurred among case patients ≥18
months old.
• In November 2010, children in South Africa began receiving a
booster dose of HibCV as part of a pentavalent vaccine
• Changes in serotype distribution of Haemophilus influenzae
meningitis isolates identified through laboratory-based
surveillance following routine childhood vaccination against H.
influenzae type b in Brazil
• 3910 H. influenzae isolated from cerebrospinal fluid or blood
from meningitis cases from 1990 to 2008 were analysed.
• Hib accounted for 98% of H. influenzae meningitis isolates
received during 1990–1999 versus 59% during 2000–2008
• Non-b serotypes increased from 1% to 19%
• NTHi increased from 2% to 22%
• Higher proportions of non-b serotypes and NTHi than Hib
were isolated from blood rather than cerebrospinal fluid
4 important conclusions…
1. A shift in the distribution of capsular serotypes of invasive H.
influenzae disease has occurred, with nontypeable strains
replacing type b strains as the most common blood- stream
isolates.
2. Shift in the peak age incidence: The most common disease
manifestation of invasive H. influenzae infection is
bacteremia caused by nontypeable strains in adults
3. Infections caused by encapsulated non-type b serotypes,
especially serotypes a and f, have been observed in selected
geographic regions.
4. Selected studies suggest an increasing incidence of invasive
H. influenzae infection, particularly by nontypeable strains.
IMMUNOGLOBULIN DEFICIENCY IN
CHILDREN WITH HIB VACCINE
FAILURE
• This study aimed to estimate the prevalence of
immunoglobulin deficiency in children with Hib vaccine
failure several years after infection
• A completed questionnaire and blood sample was
provided by 170 children at a median of 4 years after
infection
• 19 (11.2%) children had immunoglobulin deficiency, including
IgA (n = 12), IgM (n = 5) and all three immunoglobulin classes
(n = 2).
• Immunoglobulin deficiency was associated with younger age
(<2 years) at initial Hib disease &
• Parental reporting of their child receiving >2 antibiotic courses
annually in early childhood
Vaccine failure
• Enhanced surveillance of Hib vaccine failure cases in the
UK between 1992 and 1998 revealed that around 20% of
children had co-morbidities including prematurity,
malignancy, developmentaldelay, Down syndrome and
neutropenia .
• In addition, enhanced national surveillance revealed that
21% of 106 children immunised with the Hib conjugate
vaccine in infancy had Ig deficiency when tested after
recovery from their acute infection
Clinical and immunological risk factors associated with Haemophilus influenzae type b
conjugate vaccine failure in childhood. Clin Infect Dis 2000;31:973–80.
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Accelerating introduction of new vaccines: barriers to
introduction and lessons learned from the recent type b
vaccine experience Haemophilus influenzae. Rana Hajjeh ,
Phil. Trans. R. Soc. B 2011, 366, 2827-2832
3 major areas of focus:
communications to increase awareness about the various
factors needed for evidence-based decisions that meet a
country’s health goals
research activities to answer key questions that support
vaccine introduction and long-term programme sustainability
coordination with the various stakeholders at global, regional
and country levels to ensure successful programme
implementation.