Safety of and Immune Response to an H1N1 Influenza Vaccine in HIV Infected Pregnant Women

Study Overview
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Brief Summary
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Both pregnant women and people infected with HIV are at increased risk of viral infection, including influenza infection. Pregnant women infected with HIV may be at particular risk of infection from the new H1N1 influenza virus. This study tested the safety and immunogenicity of an H1N1 influenza vaccine in pregnant women infected with HIV.

Detailed Description
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On June 11, 2009, the World Health Organization declared a pandemic of the new H1N1 influenza virus, after the virus had caused significant fevers and respiratory illnesses in Mexico and the United States. Pregnant women are at an increased risk of complications from influenza. HIV infected people tend to have lower than normal antibody responses to seasonal influenza vaccines. Data suggest that larger than average doses of a vaccine counteract a weak antibody response. Preliminary results from ongoing studies of influenza A (H1N1) 2009 monovalent vaccines indicate that the vaccine may increase immune activation. This study tested the safety and antibody response of high doses of the influenza A (H1N1) 2009 monovalent vaccine in pregnant women infected with HIV. Participation in this study lasted until 6 months after participants had delivered their babies or up to 52 weeks. Participants received two doses of the H1N1 vaccine at study entry and after 21 days. Each dose consisted of two intramuscular injections (four total injections). On the days of the injections, participants had their babies' heart rates checked before and after vaccination. At these visits, and at follow-up visits on Days 21, 31, and 42, participants completed a review of symptoms, physical and neurological exams, and a blood draw. For 10 days after receiving each dose of the vaccine, participants were asked to keep track of their temperatures and symptoms or reactions in a journal. Participants were contacted on Day 2 and Day 10 after the first dose of vaccine was given and on Day 2 after the second dose of vaccine was given. Some participants also received a phone call after 6 months. At delivery of each participant's baby, blood was drawn from both the mother and umbilical cord (or from the baby if the cord blood could not be obtained). At 3 and 6 months after delivery, participants came in for follow-up visits involving, for both mother and child, a review of symptoms, brief physical exams, and blood draws (at 6 months only some women had a clinic visit, the rest received a phone call).

Official Title
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A Phase II Study to Assess the Safety and Immunogenicity of an Inactivated Monovalent Influenza A (H1N1) Vaccine in HIV-1 Infected Pregnant Women

Conditions
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HIV Infections, H1N1 Influenza Virus

Intervention / Treatment
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* Biological: Influenza A (H1N1) monovalent vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Step I: Confirmed diagnosis of HIV-1 infection Pregnant Between 14 and 35 weeks of gestation Documented platelet count of greater than 50,000 mm3 and an absolute neutrophil count (ANC) of greater than 500 mm3 within 28 days prior to study entry Able to understand and comply with planned study procedures On antiretroviral therapy (ART) as outlined in the treatment guidelines for pregnant HIV-1 infected women. Women must be currently taking ART or should initiate ART either prior to or concomitantly with the first dose of the vaccine. Inclusion Criteria for Step II: Received the first dose of influenza A (H1N1) 2009 monovalent vaccine Has a documented platelet count of greater than 50,000 mm3 and an ANC of greater than 500 mm3 within the 28 days prior to Step II entry Exclusion Criteria for Step I: Has a known allergy to eggs, egg products, neomycin, or polymyxin Has a history, in the opinion of the site investigator, of severe reactions following previous immunization with seasonal TIV Participation in a novel H1N1 influenza vaccine study in the past 2 years Proven history, by reverse transcription polymerase chain reaction (RT-PCR), of novel influenza H1N1 infection or positive influenza diagnostic test since June 2009 (specificity to H1N1 not required) prior to study entry Received any other live licensed vaccine within 4 weeks or inactivated licensed vaccine within 2 weeks prior to study entry Received a nonlicensed agent (vaccine, drug, biologic, device, blood product, or medication) within 4 weeks prior to vaccination in this study or expects to receive another nonlicensed agent before delivery Acute illness and/or an oral temperature greater than or equal to 100.0 degrees F within 24 hours prior to study entry Use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months of study enrollment or has immunosuppression as a result of an underlying illness or treatment (other than HIV-1 infection) Active neoplastic disease (excluding nonmelanoma skin cancer, human papillomavirus [HPV]-related cervical dysplasia, and cervical intraepithelial neoplasia [CIN] Grades 1, 2, or 3) Long-term use of glucocorticoids, including oral or parenteral prednisone or equivalent (at least 2.0 mg/kg per day or at least 20 mg total dose) for more than 2 consecutive weeks (or 2 weeks total) in the past 3 months or high-dose inhaled steroids (more than 800 mcg/day of beclomethasone dipropionate or equivalent) within the past 3 months. Nasal and topical steroids are allowed. Received immunoglobulin or other blood products (with exception of Rho D immune globulin) within the 3 months prior to enrollment in this study Current diagnosis of uncontrolled major psychiatric disorder History of Guillain-Barre syndrome in the subject or subject's family (including parents, siblings, half-siblings, or children) Onset of a neurological disorder including (but not limited to) absent ankle and patellar deep tendon reflexes (DTRs) in both legs (all four absent) within the past 6 months Disproportionate loss of strength in lower extremity or extremities compared to the upper extremities (not thought to be related to pregnancy) within the past 6 months Any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. Pregnancy complications such as preterm labor, hypertension and pre-eclampsia are not exclusion criteria for this study. Exclusion Criteria for Step II: Received a nonlicensed agent (vaccine, drug, biologic, device, blood product, or medication), other than from participation in this study, since the study vaccine dose #1 or expects to receive another nonlicensed agent before delivery Use of anti-cancer chemotherapy or radiation therapy since study vaccine dose #1, new diagnosis of an active malignancy, or is immunosuppressed as a result of an underlying illness (other than HIV-1 infection) or treatment Use of glucocorticoids, including oral or parenteral prednisone or equivalent (at least 2.0 mg/kg per day or at least 20 mg total dose) or high-dose inhaled steroids (more than 800 mcg/day of beclomethasone dipropionate or equivalent) for more than 2 consecutive weeks (or 2 weeks total) since study vaccine dose #1. Nasal and topical steroids are allowed. Received immunoglobulin or other blood products (with exception of Rho D immune globulin) since study vaccine dose #1 A new diagnosis of uncontrolled major psychiatric disorder since study vaccine dose #1 New occurrence or new awareness of Guillain-Barre syndrome in the subject or subject's family (including parents, siblings, half-siblings, or children) since study vaccine dose #1 A new onset of a neurological disorder including (but not limited to) absent ankle and patellar DTRs in both legs (all four absent) since study vaccine dose #1 Disproportionate loss of strength in lower extremity or extremities compared to the upper extremities (not thought to be related to pregnancy) since study vaccine dose #1 Any Grade 3 toxicity or AE experienced by a participant unless the investigator has received protocol team approval Any Grade 4 toxicity or AE (other than injection site reaction or fever) that is definitely, probably, or possibly related to the study vaccine dose #1 Any Grade 4 injection site reactions or fever experienced by a subject, unless the investigator has received protocol team approval Any Grade 4 AEs that are definitely not or probably not related to study vaccine, unless the investigator has received protocol team approval Any new clinical findings since the study vaccine dose #1, that, in the investigator's opinion, would compromise the safety of the participant Participant refuses further vaccination. The subject will still be asked to complete safety visits and be followed in the study. Participant withdraws consent. Participants may withdraw their consent for study participation at any time and for any reason, without penalty.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H1N1 vaccine<br>Pregnant women enrolled received two doses of H1N1 vaccine, administered 21 days apart. | Biological: Influenza A (H1N1) monovalent vaccine<br>* Two 15-microgram intramuscular vaccine injections given together form one dose; two doses (four total injections) are given 21 days apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Who Had at Least One Adverse Event (AE) | Shows the number of participants who had at least one adverse event (AE) in each category. These include: abnormal laboratory values, signs and symptoms, or diagnoses; solicited local AEs; and solicited systemic AEs. Adverse Events were graded using the DAIDS Grading Severity of AEs (see Link under More Information), as follows: grade 1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death. | Measured up to 6 months after delivery | 
| The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine | Shows the number of participants who experienced any events that were thought to be at least possibly related to study treatment. Adverse Events were graded using the DAIDS Grading Severity of AEs (see Link under More Information), as follows: grade 1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death. | Measured up to 6 months after delivery | 
| Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose |  | Measured at Day 21 | 
| Percent of Pregnant Women With a Hemagglutination Inhibition (HAI) Titer of >= 40 | Antibodies to Influenza A (H1N1) 2009 were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280. Seroprotection was defined as having a titer of >=40 following vaccination. | Measured at 21 days after first dose and at 10 days after second dose of study vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Pregnant Women With an HAI Titer of >= 40 at Delivery, 3 Months and 6 Months After Delivery | Antibodies to Influenza A (H1N1) 2009 were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280. Seroprotection was defined as having a titer of >=40 following vaccination. | Measured at delivery of the baby, and at 3 months and 6 months after delivery | 
| Percent of Infants With an HAI Titer of >= 40 | Antibodies to Influenza A (H1N1) 2009 were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280. Seroprotection was defined as having a titer of >=40 following vaccination. | Measured at birth (via cord blood) and at 3 months and 6 months of age | 
| Maternal Geometric Mean Titers (GMT) of Antibodies HAI | Presents the value of the geometric mean titer at each time point. Antibodies to Influenza A (H1N1) 2009 were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280. | Measured after the first and second doses of the vaccine, at delivery, and at 3 and 6 months after delivery | 
| Infant GMT of Antibodies HAI | Presents the value of the geometric mean titer at each time point. Antibodies to Influenza A (H1N1) 2009 were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280. | Measured at birth and at 3 and 6 months of age | 
| Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | The median and interquartile range (IQR) of B-Cell ELISPOT-measured IgG antibody-secreting cells (ASC)/10^6 PBMC and the median and interquartile range (IQR) of T-Cell ELISPOT-measured pH1N1 IFNgamma spot-forming cells (SFC)/10^6 PBMC. | Measured at entry, at 21 days after first dose of vaccine, at 10 days after second dose | 
| Response to Seasonal Trivalent Influenza Vaccine (TIV) | Presents the value of the median titer as well as the interquartile range at study entry. Antibodies to seasonal Influenza vaccine were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280. | Measured at entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccine, Pregnant, Perinatal