1. Hib Vaccines: What is new ?? A Review
Dr S G Kasi
Bengaluru

2. 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

3. Improved Hib vaccines :

4. 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,
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.

5. 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
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).

6. New combos with hib & Combos containing DTaP+IPV+Hib combined with other infant vaccines

7. 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,
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

8. 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.

9. One-year post-primary antibody persistence and booster immune response to a DTaP-IPV//PRP~T vaccine (Pentaxim) given at 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:
A DTaP-IPV//PRP~T vaccine,was given to 182 healthy children in South Africa at 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 anti-pertussis antibody titres
The DTaP-IPV//PRP~T vaccine booster was well tolerated, with fever ≥39.0°C in only 1.7% of participants

10. 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 B-inactivated poliovirus-Haemophilus influenzae type b (DTPw-HBV-IPV/Hib) vaccine versus co-administration of DTPw-HBV/Hib and IPV vaccines in 12 to 24 month old Filipino toddlers
Human Vaccines. Volume 8, Issue 3   March 2012

11. 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.

12. 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

13. Co administration with Hep A vaccine
Immunogenicity and safety of an inactivated hepatitis A vaccine when coadministered with Diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines in children 15 months of age. Pediatr Infect Dis J 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

14. 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 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

15. HibMenCY
Immunogenicity and Safety of H influenza Type b N meningitidis C/Y Conjugate Vaccine in Infants Pediatrics ;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.

16. 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.

17. 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)

18. Effectiveness data on Hib vaccines

19. Effectiveness of Haemophilus Influenzae Type B Conjugate Vaccine for Prevention of Meningitis in Senegal Pediatric Infectious Disease Journal: May Vol 30 Issue 5 - pp
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

20. Chile & Columbia: No Booster , Uruguay & Argentina : With Booster

21. Cost-effectiveness data on Hib vaccines

22. 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.

23. 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

24. Changes in Hib epidemiology following use of Hib vaccines

25. Current Epidemiology and Trends in Invasive Haemophilus influenzae Disease—United States, – Clin Infect Dis. (2011) 53 (12):

26. Changes in Hib epidemiology 1
Between 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

27. 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 population in 1989 to 0.25 cases per population in 2008; 317% increase)
Serotype f was observed primarily among adults, with 83% of cases reported in adults aged 18 years.

28. 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

29. Invasive Haemophilus influenzae in British Columbia: non-Hib 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
 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 ampicillin-resistant (BLNAR) strains

30. Invasive disease due to Haemophilus influenzae serotype b ten years after routine vaccination, South Africa, 2003–2009. Vaccine
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

31. 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

33. 4 important conclusions…
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.
Shift in the peak age incidence: The most common disease manifestation of invasive H. influenzae infection is bacteremia caused by nontypeable strains in adults
Infections caused by encapsulated non-type b serotypes, especially serotypes a and f, have been observed in selected geographic regions.
Selected studies suggest an increasing incidence of invasive H. influenzae infection, particularly by nontypeable strains.

34. Immunoglobulin deficiency in children with hib vaccine failure

35. 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 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

36. Vaccine failure
Enhanced surveillance of Hib vaccine failure cases in the UK between and 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 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.

37. 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,
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.

39. Fully liquid DTaP5-IPV-Hib + PCV7 compared with DTaP3-IPV/Hib + PCV7
Fully liquid DTaP5-IPV-Hib + PCV7 compared with DTaP3-IPV/Hib + PCV7. Vaccine Volume 29, Issue 43, 6 October 2011, Pages
Immunogenicity and safety of a Haemophilus influenzae B (Hib)–hepatitis B vaccine with a modified process hepatitis B component administered with concomitant pneumococcal conjugate vaccine to infants.

40. Mean annual incidence of H. influenzae infection was 1
Mean annual incidence of H. influenzae infection was 1.62 cases per population;(redn of 92%)
15.3% of cases were fatal
Incidence was higher among adults aged ≥65 years, compared with other age groups
The largest burden of disease among children aged <5 years was in infants aged <1 year; many of these cases occurred during the first month of life in preterm or low–birth weight infants.
10% of the total burden of disease among children aged <5 years occurred in American Indian and Alaska Native children
Small increases in the incidence of serotypes a, e, and f were observed during 1989–2008.