Hib Vaccines: A Review

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