Safety and Immunogenicity of Anti-Pneumococcal Vaccines in HIV-Infected Pregnant Women

Study Overview
=================
Brief Summary
-----------------
The purpose of this study was to determine the safety, reactogenicity, immunogenicity, transplacental antibody transfer and interference with infant responses to childhood vaccination of maternal vaccination with pneumococcal conjugate 10-valent vaccine (PCV-10) or pneumococcal polysaccharide 23-valent vaccine (PPV-23) by comparison with placebo.

Detailed Description
-----------------
This was a multi-center, Phase II, randomized, double-blinded, placebo-controlled study of Human Immunodeficiency Virus (HIV)-infected pregnant women on Highly Active Antiretroviral Therapy (HAART) who were in the second or third trimester of pregnancy and of their infants. The study was designed to investigate the safety, reactogenicity, immunogenicity, transplacental antibody transfer and interference with infant responses to childhood vaccination of maternal vaccination with PCV-10 or PPV-23 by comparison with placebo. Mothers were randomized to one of three arms and received PCV-10, PPV-23, or placebo in a blinded fashion. They were followed for safety, immunogenicity and vaccine-specific anti-capsular pneumococcus (PNC) antibody persistence until 24 weeks post-delivery. Women who received placebo were randomized to a second study step and received PCV-10 or PPV-23 at 24 weeks post-delivery. Antibody responses to the vaccine administered 6 months postpartum were measured. Women who received placebo but cannot be randomized to a second study step due to ongoing new pregnancy were enrolled in a third study step and receive open label PCV-10 at the last study visit; no data were collected on these women and they were not followed after vaccine administration. All infants received PCV-10 vaccinations per local standard of care.

Official Title
-----------------
Safety and Immunogenicity of Anti-Pneumococcal Vaccines in HIV-Infected Pregnant Women

Conditions
-----------------
PNC Vaccine, HIV-infected Pregnant Women

Intervention / Treatment
-----------------
* Biological: PPV-23
* Biological: PCV-10
* Other: NaCl


Participation Criteria
=================
Eligibility Criteria
-----------------
Step 1 Inclusion Criteria for Pregnant Women: Pregnant women ≥ 18 years old who provided written informed consent prior to study initiation. Pregnant women < 18 years old with parent or legal guardian able and willing to provide signed informed consent, or who had the capacity to consent for themselves, as defined by the local Institutional Review Board (IRB), and who provided written informed consent prior to study initiation. Gestational age [≥ 14 weeks (14 weeks 0 days) to < 33 weeks (32 weeks 6 days)] documented by the approximate date of the last menstrual period and corroborated by ultrasound if obtained as per local standard of care. Results of the ultrasound were recorded on the Abdominal Ultrasound Form. Documentation of HIV-1 infection defined as positive results from two samples collected at different time points as per standard of care. Results and source documentation may have been obtained from the medical records. Receipt of HAART (a regimen of at least three ARV drugs) for ≥ 4 weeks prior to enrollment. Documented platelet count of > 50,000/mm3 and an absolute neutrophil count (ANC) of > 500/ mm3 ≤ 28 days prior to study entry. Women who were willing and able to comply with the study visits. Step 1 Exclusion Criteria for Pregnant Women: Receipt of any PCV or PPV-23 at any time prior to enrollment, documented by medical history or record. Receipt of any live licensed vaccine ≤ 4 weeks or inactivated licensed vaccine ≤ 2 weeks prior to study entry. Receipt of a non-licensed agent (vaccine, drug, biologic, device, blood product, or medication) ≤ 4 weeks prior to enrollment in this study, or expectations to receive another non-licensed agent before delivery unless approval from the protocol team is obtained. Any significant (in the opinion of the site investigator) acute illness and/or oral temperature greater than or equal to 100.4 degrees F ≤ 24 hours prior to study entry. Women who planed to terminate their pregnancy. Women who had a prior history of lupus or other autoimmune disorders. Use of anti-cancer systemic chemotherapy or radiation therapy ≤ 48 weeks of study enrollment, or evidence of immunosuppression as a result of an underlying illness (other than HIV-1 infection) or treatment. Ongoing neoplastic disease (excluding non-melanoma skin cancer, and human papilloma virus-related cervical dysplasia, cervical intraepithelial neoplasia (CIN) grades 1, 2 or 3). Long term use of glucocorticoids, including oral or parenteral prednisone ≥ 20 mg/day or equivalent for more than 2 consecutive weeks (or 2 weeks total) within 12 weeks of study entry. Women who received last dose of corticosteroids for preterm labor ≤ 1 week prior to study entry. Note: A woman can be enrolled if more than 1 week has elapsed from the last dose of corticosteroids, i.e., enrollment may be delayed to satisfy this criterion. Receipt of immunoglobulin or other blood products (with exception of Rho D immune globulin) ≤ 12 weeks prior to enrollment in this study or is scheduled to receive immunoglobulin or other blood products (with the exception of Rho D immune globulin) during pregnancy or for the first 24 weeks after delivery. Receipt of Interleukin-2 (IL2), interferon (IFN), granulocyte-macrophage colony-stimulating factor (GMCSF) or other immune mediators ≤ 12 weeks before enrollment. History of a severe adverse reaction to inactivated polysaccharide or conjugated vaccines. Any condition that would, in the opinion of the site investigator, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol. Pregnancy complications (in the current pregnancy) such as pre-term labor, and pre-eclampsia or any other pregnancy related complication, which in the opinion of the investigator might jeopardize the results of the study. Chronic hepatitis B infection that may require administration of Hepatitis B Hyperimmune Globulin to neonates. Step 2 Inclusion Criteria for Women: 24 weeks ± 4 weeks postpartum. Completion of Step 1. Receipt of placebo on Step 1. Step 2 Exclusion Criteria for Women: Pregnancy. Receipt of any live licensed vaccine ≤ 4 weeks or inactivated licensed vaccine ≤ 2 weeks prior to Step 2 entry. Receipt of a non-licensed agent (vaccine, drug, biologic, device, blood product, or medication) ≤ 4 weeks prior to vaccination, or expects to receive another non-licensed agent within 28 days after vaccination. Any significant (in the opinion of the site investigator) acute illness and/or oral temperature greater than or equal to 100.4 degrees F within 24 hours of entry except when, in the opinion of the physician, withholding the agent entails even greater risk. Use of anti-cancer systemic chemotherapy or radiation therapy or has developed immunosuppression as a result of an underlying illness (other than HIV-1 infection) or treatment. Use of glucocorticoids, including oral or parenteral prednisone ≥ 20 mg/day or equivalent for more than 2 consecutive weeks (or 2 weeks total) within 2 weeks of entry in Step 2. Receipt of immunoglobulin or other blood products (with exception of Rho D immune globulin) within 12 weeks prior to entry in Step 2 or is scheduled to receive immunoglobulin or other blood products (with the exception of Rho D immune globulin) during the 28 days following vaccination. Receipt of IL2, IFN, GMCSF or other immune mediators ≤ 12 weeks before entry in Step 2. Step 3 Inclusion Criteria for Women 24 weeks ± 4 weeks postpartum. Completion of Step 1. Receipt of placebo on Step 1. Met Step 2 exclusion criterion of pregnancy. Step 3 Exclusion Criteria for Women None.
Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1A (PPV-23)<br>In Step 1, women in Arm 1A were administered a 0.5 milliliter (mL) dose of PPV-23 intramuscularly once. | Biological: PPV-23<br>* PPV-23 was a polysaccharide PNC vaccine, licensed in Brazil, directed against 23 serotypes.<br>|
| Experimental: Arm 1B (PCV-10)<br>In Step 1, women in Arm 1B were administered a 0.5 mL dose of PCV-10 intramuscularly once. | Biological: PCV-10<br>* PCV-10 was a conjugate PNC vaccine, licensed in Brazil, directed against 10 serotypes.<br>|
| Placebo Comparator: Arm 1C (placebo)<br>In Step 1, women in Arm 1C were administered a 0.5 mL dose of 0.9 percent Sodium Chloride (NaCl) intramuscularly once. | Other: NaCl<br>* NaCl was the placebo for the study against which the two vaccines were compared during pregnancy.<br>|
| Experimental: Arm 2A (PPV-23)<br>In Step 2, women who received placebo in step 1 that were randomized to Arm 2A were administered a 0.5 mL dose of PPV-23 intramuscularly once. | Biological: PPV-23<br>* PPV-23 was a polysaccharide PNC vaccine, licensed in Brazil, directed against 23 serotypes.<br>|
| Experimental: Arm 2B (PCV-10)<br>In Step 2, women who received placebo in step 1 that were randomized to Arm 2B were administered a 0.5 mL dose of PCV-10 intramuscularly once. | Biological: PCV-10<br>* PCV-10 was a conjugate PNC vaccine, licensed in Brazil, directed against 10 serotypes.<br>|
| Experimental: Step 3 (PCV-10)<br>In Step 3, women who received placebo in step 1 and failed entry into step 2 due to ongoing new pregnancy were administered a 0.5 mL dose of PCV-10 intramuscularly once. | Biological: PCV-10<br>* PCV-10 was a conjugate PNC vaccine, licensed in Brazil, directed against 10 serotypes.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Women Who Experienced Various Adverse Events (AEs) | The number of women who experienced grade ≥ 3 adverse events (AEs) in the 4 weeks after vaccination in Step 1 and grade 4 AEs or death up to 24 weeks post-partum. AE grading (Grade 1- mild to Grade 4-life-threatening) was done by DAIDS AE Grading table v2.0 (see References). | up to 24 Weeks Post-Delivery for mother participants. | 
| Number of Women Who Experienced Grade ≥ 3 Adverse Events (AEs) in Step 2 | The number of women who enrolled in Step 2, received vaccine and who experience grade ≥ 3 adverse events (AEs) in the 4 weeks after vaccination in Step 2 is presented. | up to 4 Weeks after Step 2 vaccination for Mother Participants | 
| Number of Infants With Various Adverse Events Following Maternal Vaccination With PCV10 and PPV23 Administered in Pregnancy | The number of infants who experience grade ≥ 3 adverse events (AEs), congenital defects, HIV infections or pneumonia, meningitis or IPD after maternal vaccination in Step 1, assessed from birth through 24 weeks of life for infant participants. | through 24 weeks of life for infant participants | 
| Number of Women With a Two-fold or Higher Increase in ELISA-measured IgG PNC Antibody Concentrations | The number of participants with a two-fold or higher increase in ELISA-measured IgG PNC antibody concentrations from baseline to 28 days after immunization in Step 1 to 1 or more serotypes. The proportion of participants with >=0.35ug/mL ELISA-measured IgG PNC antibody concentrations at 28 days after immunization in Step 1 to 1 or more serotypes. | 28 days after Immunization in Step 1 | 
| Number of Infant Participants With ELISA-measured IgG PNC Antibody Levels ≥ 0.35ug/mL at 8 Weeks of Age | The number of infant participants with ELISA-measured IgG PNC antibody levels ≥ 0.35ug/mL at 8 weeks of age to 1 or more serotypes. | 8 Weeks of Life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Infant/Mother PNC Antibody Levels | The ratios of infant/mother PNC antibody levels to study used serotypes. | At Delivery for Mother Participants and Birth for Infant Participants | 
| Number of Participants With a >=0.35ug/mL ELISA-measured IgG PNC Antibody Concentrations at Labor/Delivery and 24 Weeks Post-partum | The number of participants with a >=0.35ug/mL ELISA-measured IgG PNC antibody concentrations at the time points listed for 1 or more serotypes. | at Labor and Delivery and 24 Weeks Post-Delivery for Mother Participants | 
| Number of Participants With a Two-fold or Higher Increase in ELISA-measured IgG PNC Antibody Concentrations at 28 Days After PPV-23 Vaccination in Step 1 and Step 2 | The number of participants with a two-fold or higher increase in ELISA-measured IgG PNC antibody concentrations from baseline to 28 days after immunization in Step 1 vs from entry to Step 2 to 28 days after immunization in Step 2 to 1 or more serotypes. | 28 days after Immunization in Step 1 and in Step 2 | 
| Number of Participants With a Two-fold or Higher Increase in ELISA-measured IgG PNC Antibody Concentrations at 28 Days After PCV-10 Vaccination in Step 1 and Step 2 | The proportion of participants with a two-fold or higher increase in ELISA-measured IgG PNC antibody concentrations from baseline to 28 days after immunization in Step 1 vs from entry to Step 2 to 28 days after immunization in Step 2 to 1 or more serotypes. | 28 days after Immunization in Step 1 and in Step 2 | 
| Number of Infant Participants With ELISA-measured IgG PNC Antibody Levels ≥ 0.35ug/mL at 16 and 24 Weeks of Age | The number of infant participants with ELISA-measured IgG PNC antibody levels ≥ 0.35ug/mL at 16 and 24 weeks of age to 1 or more serotypes. | at weeks 16 and 24 of life | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PPV-23, PCV-10, HIV, Immunization, Pregnancy