Protocol No: ECCT/20/04/03 Date of Protocol: 08-01-2020

Study Title:

Study Title: Safety and Immunogenicity Study of Full Schedule (3-Dose SHAN6™) or SHAN6™- SHAN 5®- SHAN6™ Versus the Licensed Vaccine SHAN 5® With bOPV and IPV When Administered Per National Immunization Schedule in Healthy Kenyan Infants. 

Phase III, multi-center, randomized, active-controlled, open-label, three-arm, study in 690 infants who will receive a 3-dose primary series at 6, 10 and 14 weeks of age, of either 3-dose SHAN6™ or SHAN6™ – SHAN 5® + bOPV – SHAN6™ or SHAN 5® + bOPV – SHAN 5® + bOPV – SHAN 5® + bOPV + IPV, and a booster dose of either SHAN6™ or SHAN 5® + bOPV at 18 months of age

Study Objectives:

Primary Objective:The first primary objective is to demonstrate the non-inferiority of SHAN6™ compared to the licensed control vaccines SHAN 5® (+ bOPV + IPV) with respect to the adjusted Geometric Mean Concentration (aGMC) ratio for anti-pertussis toxoid (PT) and anti-fimbriae (FIM) for pertussis and seroprotection rates for all other antigens 28 days after a three-dose primary series (6, 10 and 14 weeks).

If the first objective is reached, the second primary objective is to demonstrate the non-inferiority of mixed schedule administration of SHAN6™ and SHAN 5® (+ bOPV) compared to SHAN 5® (+ bOPV + IPV) as a three dose primary series with respect to the aGMC ratio for anti-PT and anti-FIM for pertussis and seroprotection rates for all other antigens 28 days after a three-dose primary series.

Secondary Objective:

Immunogenicity

• To describe the immunogenicity profile of SHAN6™ vaccine three dose series and that of the control vaccines SHAN 5® (+ bOPV + IPV).

• To describe the immunogenicity profile of mixed schedule administration of SHAN6™ and SHAN 5® (+ bOPV).

• To describe the immune response to co-administered ORV in terms of seroresponse (serum immunoglobulin [Ig]A anti-rotavirus antibody levels) in a randomized subset of subjects in each study group.

• To describe the immune response to co-administered PCV in terms of serum antipneumococcal IgG for the 10 vaccine serotypes in a randomized subset of subjects in each study group.

• To describe the immunogenicity profile, 28 days after the single booster dose of SHAN6™ or SHAN 5® (+ bOPV) in each study group.

Safety

To describe the safety profile, 28 days after each and any dose of SHAN6™ vaccine and that of the control vaccines SHAN 5® (+ bOPV + IPV), following the primary series and booster vaccination

Laymans Summary:

A combined vaccine is a vaccine that is designed to protect against two or more diseases or against one disease caused by different strains or serotypes of the same organism1. Combination vaccines are an effective means of decreasing the number of injections and simplifying the immunization schedule, thus providing overall benefits to infants, parents, healthcare providers, office managers, and managed care administrators. The investigational vaccine, SHAN6™ (DTwP-HepB-Hib-IPV) is a combination of six antigens: Diphtheria toxoid (DT), Tetanus toxoid (TT), Whole cell pertussis (wP), recombinant Hepatitis B surface antigen (HepB), Haemophilus influenzae type b (Hib) [Polyribosyl Ribitol Phosphate (PRP) conjugated to tetanus toxoid] and trivalent Inactivated poliovirus vaccine (IPV)4.SHAN6™ combination vaccine has been developed in order to comply with recommended immunizations in infancy as it will simultaneously enhance the protection against several infections with a reduced number of injections and at costs affordable to many developing countries. Therefore, it supports one of the objectives of the Polio Eradication and Endgame Strategic Plan 2013-2018, which calls for the introduction of at least one dose of inactivated polio vaccine (IPV) into routine immunization. The Study will be conducted in Nairobi , Kisumu and Siaya Counties, A total of 690 children are planned to take part in the study for a duration of 17.5 months. Children by chance will assigned, like flipping a coin, to receive a primary vaccination course of 3 doses of either SHAN6™ investigational vaccine; or mixed administration of SHAN6® and the licensed pentavalent control vaccine SHAN 5® (together with commercial bivalent oral poliovirus vaccine [bOPV]); or the licensed control vaccines SHAN 5® (with bOPV at each dose) and inactivated poliovirus vaccine (IPV) at the time of the third dose only. All children who participate will receive vaccines currently recommended in the Kenyan National Immunization Schedule at the same time as SHAN 5® or SHAN6™; pneumococcal conjugate vaccine (PCV) and oral rotavirus vaccine (ORV). Additionally, children in all three groups will be assigned to receive a booster dose of either SHAN6™ or SHAN 5® (together with commercial poliovirus vaccine) at 18 months of age.

Abstract of Study:

Vaccines are cost-effective public health tools for the prevention and control of infectious diseases . Their routine use has enormous impact on tetanus , diphtheria , pertussis (whooping cough) , poliomyelitis , hepatitis B (Hep B) and invasive Haemophilus influenzae type b (Hib) diseases . However, there are still global disparities with regard to vaccine use and coverage, associated mainly with inequalities in the access to health care services. To improve the delivery of vaccines to infant populations, combination vaccines are regarded as an important tool allowing the concomitant administration of several antigens in a single injection. Combination vaccines can also reduce the cost of the delivery of immunization programs and increase compliance with vaccination . The prevention of diphtheria, tetanus, pertussis, hepatitis B, invasive infections due to Hib and poliomyelitis are major goals that could be achieved only if a constant high level of immunization coverage is maintained in the population. The combination vaccines are one of the important tools in achieving this. Sanofi Healthcare India Private Limited (SHIPL)is developing a fully liquid hexavalent vaccine, DTwP-HepB-Hib-IPV, SHAN6™. This investigational vaccine, SHAN6™, is a combination of six antigens: DT and TT, wP, recombinant hepatitis B surface antigen (HBsAg), Hib (PRP) conjugated to tetanus toxoid and trivalent IPV. All the Drug Substances required for the manufacture of SHAN6™ are produced in Industrial Operations (I/O) suites at SHIPL using the similar manufacturing process as followed in SHAN 5®. However, • The PRP used in the manufacture of PRP-T and the trivalent IPV bulk are procured from Sanofi Pasteur (Site: Marcy l’Etoile, France) • wP is manufactured using the similar process (except for inactivation step) as that used for SHAN 5® • Recombinant HBsAg (expressed using the Hansenula polymorpha expression system) is obtained from Sanofi Pasteur (Site: Pilar, Argentina). The overall formulation process for SHAN 5® and SHAN6™ is similar, until the addition of IPV in SHAN6™ at the last step. IPV 1, 2 and 3 antigens, similar to the strains used in SHANIPV™, have been added to these antigens to produce the final formulation of SHAN6™. The first primary objective of the study is to demonstrate the non-inferiority of SHAN6™ compared to the licensed control vaccines SHAN 5® (+ bOPV + IPV) with respect to the adjusted Geometric Mean Concentration (aGMC) ratio for anti-pertussis toxoid (PT) and anti-fimbriae (FIM) for pertussis and seroprotection rates for all other antigens 28 days after a three-dose primary series (6, 10 and 14 weeks). If the first objective is reached, the second primary objective is to demonstrate the non-inferiority of mixed schedule administration of SHAN6™ and SHAN 5® (+ bOPV) compared to SHAN 5® (+ bOPV + IPV) as a three dose primary series with respect to the aGMC ratio for anti-PT and anti-FIM for pertussis and seroprotection rates for all other antigens 28 days after a three-dose primary series. This will be a Phase III, randomized, open-label, multi-center, study in 690 Kenyan infants aged 6-8 weeks. The infants will be randomly allocated, at 1:1:1 ratio, to receive 3 doses of SHAN6™ vaccine, or mixed administration of SHAN6™ and SHAN 5® (with bivalent oral polio vaccine [bOPV]), or the licensed control vaccine SHAN 5® (with bOPV and inactivated polio vaccine [IPV]). Additionally, infants in all three groups would be randomly allocated to receive a booster dose of either SHAN6™ or SHAN 5® with bOPV at 18 months. Accordingly, there will be 3 study groups (A, B, and C) for primary series and 2 for Booster as described in the protocol. The investigational or control vaccines will be co-administered with other pediatric vaccines (PCV and ORV), as per the schedule prescribed by the Manufacturer and the National Immunization Schedule of Kenya. A randomized subset of 115 subjects in each group (345 overall, half of the included subjects) will be tested for the immune response against rotavirus antigens. The other subset of 115 subjects in each group will be tested for the immune response against pneumococcal antigens.