Evaluation of the Non-Inferiority of a 12-Valent Pneumococcal Conjugate Vaccine in Healthy Children in Brazil.

A Phase 3, Randomized, Partially-Blind, Clinical Trial to Evaluate the Non-Inferiority of a 12-Valent Pneumococcal Conjugate Vaccine in Healthy Children in Brazil, Compared to 10- and 13-Valent Pneumococcal Conjugate Vaccines

The purpose of this phase III study is to demonstrate immunologic non-inferiority in terms of proportion of individuals with antibody concentration ≥0.2 µg/mL (by modified 22F-inhibition enzyme-linked immunosorbent assay, ELISA) or in terms of ELISA geometric mean concentrations (GMC) of serotype-specific IgG, of 12-valent pneumococcal polysaccharide conjugate vaccine (12Pn-PD-DiT-CRM, hereby indicated as PCV12), containing the serotypes 1, 4, 5, 6B, 7F, 9V, 14, and 23F conjugated with non-typeable Haemophilus influenzae protein D, 19F conjugated with TD, 18C conjugated with TT, and 6A and 19A conjugated with CRM197, and to assess its safety in the population of infants vaccinated from 2 months of age with a primary regimen of 2 or 3 doses plus a booster administered at one year of life.

The purpose of this phase III study is to demonstrate immunologic non-inferiority in terms of proportion of individuals with antibody concentration ≥0.2 µg/mL (by modified 22F-inhibition enzyme-linked immunosorbent assay, ELISA) or in terms of ELISA geometric mean concentrations (GMC) of serotype-specific IgG, of 12-valent pneumococcal polysaccharide conjugate vaccine (12Pn-PD-DiT-CRM, hereby indicated as PCV12), containing the serotypes 1, 4, 5, 6B, 7F, 9V, 14, and 23F conjugated with non-typeable Haemophilus influenzae protein D, 19F conjugated with TD, 18C conjugated with TT, and 6A and 19A conjugated with CRM197, and to assess its safety in the population of infants vaccinated from 2 months of age with a primary regimen of 2 or 3 doses plus a booster administered at one year of life. Hence, this study will provide non-inferiority evidence for possible approval of a new pneumococcal vaccine in Brazil and its eventual inclusion in the national immunization program (PNI). PCV12 will be produced in national facilities, after transfer of technology to Bio-Manguinhos/Fiocruz, thus ensuring continuous provision to the public healthcare system (SUS).

This study is designed to demonstrate the immunologic non-inferiority of the PCV12 for each one of the 12 vaccine pneumococcal serotypes, when compared to the licensed vaccines GSK Synflorix® (PCV10) and Pfizer's/Wyeth's Prevenar 13® (PCV13). PCV10 will be used for the comparison of the immune response to the 10 common serotypes. PCV13 or the least immunogenic serotype of PCV10 will be used for the comparison of the immune response to the two additional pneumococcal serotypes 19A and/or 6A conjugated to CRM197.

The non-inferiority of PCV12 will be evaluated in the two schedules recommended in Brazil, the 2+1 scheme (followed by PNI) or the 3+1 scheme (the reference schedule when evaluating new vaccines).

Inclusion Criteria:

1. Male or female subjects, 6-12 weeks of age, inclusive, at the time of the first vaccination.

2. Healthy subjects as established by medical history and clinical examination before entering into the study.

3. Subjects who the investigator believes that parent(s)/ Legally Acceptable Representative(s) [LAR(s)] can and will comply with the requirements of the protocol, including:

   1. willing to provide name, address, and telephone number for contact if necessary (e.g., in case of missing a scheduled visit)
   2. available for follow-up throughout the study period
   3. capable to complete the forms for registration of signs and symptoms at home.

4. Parent(s)/LAR(s) are able to understand and sign the informed consent form.

Exclusion Criteria:

1. Preterm infants (gestation <36 weeks) or with low birth weight (<2000g).
2. Use of any investigational or non-registered product other than the study vaccines and allowed co-administered vaccines as outlined in section 3.4.9. during the entire study period. Any other vaccine administration must be discussed and approved by the medical monitor.
3. Medical history of culture- or PCR-confirmed invasive disease caused by S. pneumoniae.
4. Coagulation problems.
5. Chronic administration (more than 14 days in total) of corticosteroids, immunosuppressants or other immune-modifying drugs (except palivizumab) since birth or planned use during the study.
6. Administration of immunoglobulins and/or blood products since birth or planned use during the study period.
7. Participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product.
8. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
9. History of any reaction or hypersensitivity likely to be exacerbated by any component of the study vaccine.
10. Major congenital defects or serious chronic illness.
11. History of any seizures or any neurological disease
12. Acute disease and/or fever (axillary temperature ≥38ºC) at the time of enrolment.
13. Previous vaccination with any pneumococcal vaccine.
14. Infants born of woman who received any pneumococcal vaccine during pregnancy.