H1N1 Influenza Virus, HIV Infections
Conditions
Keywords
Vaccine, Pregnant, Perinatal
Brief summary
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
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).
Interventions
BIOLOGICALInfluenza A (H1N1) monovalent vaccine
Two 15-microgram intramuscular vaccine injections given together form one dose; two doses (four total injections) are given 21 days apart
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 39 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Who Had at Least One Adverse Event (AE) | Measured up to 6 months after delivery | 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. |
| The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine | Measured up to 6 months after delivery | 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. |
| 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 | Measured at 21 days after first dose and at 10 days after second dose of study vaccine | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | Measured at entry, at 21 days after first dose of vaccine, at 10 days after second dose | 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. |
| Percent of Pregnant Women With an HAI Titer of >= 40 at Delivery, 3 Months and 6 Months After Delivery | Measured at delivery of the baby, and at 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. |
| Response to Seasonal Trivalent Influenza Vaccine (TIV) | Measured at entry | 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. |
| Percent of Infants With an HAI Titer of >= 40 | Measured at birth (via cord blood) and at 3 months and 6 months of age | 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. |
| Maternal Geometric Mean Titers (GMT) of Antibodies HAI | Measured after the first and second doses of the vaccine, at delivery, and at 3 and 6 months after delivery | 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. |
| Infant GMT of Antibodies HAI | Measured at birth and at 3 and 6 months of age | 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. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Pregnant women were enrolled from 31 sites between October 8, 2009 and November 13, 2009.
Pre-assignment details
Two study participants were enrolled but left the clinic before receiving any vaccination and they were taken off study.
Participants by arm
| Arm | Count |
|---|---|
| H1N1 Vaccine Pregnant women received two doses of H1N1 vaccine administered 21 days apart. Each dose consisted of two 15-microgram intramuscular injections. | 128 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Not adhere to study requirements | 1 |
| Overall Study | Unable to get to clinic | 5 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | H1N1 Vaccine |
|---|---|
| Age, Continuous | 28 years STANDARD_DEVIATION 6 |
| CD4 Cells Count | 504 cells / mm^3 STANDARD_DEVIATION 264 |
| Gestational Age | 25 Weeks STANDARD_DEVIATION 6 |
| Percentage of CD4 Cells | 30 percentage of CD4 cells STANDARD_DEVIATION 11 |
| Region of Enrollment Puerto Rico | 16 participants |
| Region of Enrollment United States | 112 participants |
| Sex: Female, Male Female | 128 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 118 / 128 |
| serious Total, serious adverse events | 21 / 128 |
Outcome results
Primary
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.
Time frame: Measured at 21 days after first dose and at 10 days after second dose of study vaccine
Population: The analysis population consists of the eligible pregnant women with nonmissing HAI titers, who had not delivered prior to the evaluation, and had received all doses of vaccine up to that timepoint. The N for the analyses of HAI titers after the first and second vaccinations were 118 and 108, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| H1N1 Vaccine | Percent of Pregnant Women With a Hemagglutination Inhibition (HAI) Titer of >= 40 | Percent with titers >= 40 post dose 1 (N=118) | 73.7 Percent of participants |
| H1N1 Vaccine | Percent of Pregnant Women With a Hemagglutination Inhibition (HAI) Titer of >= 40 | Percent with titers >= 40 post dose 2 (N=108) | 80.6 Percent of participants |
Primary
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.
Time frame: Measured up to 6 months after delivery
Population: All 128 pregnant women who received at least one vaccination are included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| H1N1 Vaccine | The Number of Participants Who Had at Least One Adverse Event (AE) | Grade 4 AEs (New, after start of treatment) | 11 Participants |
| H1N1 Vaccine | The Number of Participants Who Had at Least One Adverse Event (AE) | Grade 3 AEs (New, after start of treatment) | 8 Participants |
| H1N1 Vaccine | The Number of Participants Who Had at Least One Adverse Event (AE) | Grade >=2 local and systemic AEs to injection | 0 Participants |
| H1N1 Vaccine | The Number of Participants Who Had at Least One Adverse Event (AE) | Overall (New AEs after start of treatment) | 118 Participants |
Primary
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.
Time frame: Measured up to 6 months after delivery
Population: All 128 pregnant women who received at least one vaccination are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| H1N1 Vaccine | The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine | 0 Participants |
Primary
Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose
Time frame: Measured at Day 21
Population: All 128 pregnant women who received at least one vaccination are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| H1N1 Vaccine | Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose | 0 Participants |
Secondary
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.
Time frame: Measured at birth and at 3 and 6 months of age
Population: The population consists of infants born to eligible women with nonmissing HAI titers, who had not delivered before the evaluation post second dose, and received two doses of vaccine. The N for analyses at birth, 3 and 6 months were 96, 87 and 52, respectively. Cord blood was used when available. Only some infants had a clinic visit at 6 months.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| H1N1 Vaccine | Infant GMT of Antibodies HAI | At birth (N=96 infants) | 56 units on the HAI titer scale |
| H1N1 Vaccine | Infant GMT of Antibodies HAI | At 3 months (N=87 infants) | 13 units on the HAI titer scale |
| H1N1 Vaccine | Infant GMT of Antibodies HAI | At 6 months (N=52 infants) | 14 units on the HAI titer scale |
Secondary
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.
Time frame: Measured at entry, at 21 days after first dose of vaccine, at 10 days after second dose
Population: The pregnant women who had not delivered prior to the evaluation, had received all doses of vaccine up to that timepoint and had sufficient samples for testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| H1N1 Vaccine | Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | IgG ASC/10^6 PBMC, Post Dose 2 (N=39) | 14 ASC or SFC/10^6 PBMC |
| H1N1 Vaccine | Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | pH1N1 IFNgamma SFC/10^6 PBMC, Week 0 (N=45) | 166 ASC or SFC/10^6 PBMC |
| H1N1 Vaccine | Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | IgG ASC/10^6 PBMC, Week 0 (N=36) | 6 ASC or SFC/10^6 PBMC |
| H1N1 Vaccine | Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | IgG ASC/10^6 PBMC, Post Dose 1 (N=36) | 15 ASC or SFC/10^6 PBMC |
| H1N1 Vaccine | Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | pH1N1 IFNgamma SFC/10^6 PBMC, Post Dose 1 (N=44) | 117 ASC or SFC/10^6 PBMC |
| H1N1 Vaccine | Maternal Cell-mediated Immunity (CMI) Responses, as Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | pH1N1 IFNgamma SFC/10^6 PBMC, Post Dose 2 (N=43) | 76 ASC or SFC/10^6 PBMC |
Secondary
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.
Time frame: Measured after the first and second doses of the vaccine, at delivery, and at 3 and 6 months after delivery
Population: The population consists of eligible women with nonmissing HAI titers, who had not delivered before the evaluation post first or second dose, and received all vaccines up to that point, respectively. The N for analyses after the first and second vaccinations, at delivery, 3 and 6 months after were 104, 94, 102, 92 and 58, respectively.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| H1N1 Vaccine | Maternal Geometric Mean Titers (GMT) of Antibodies HAI | Post first vaccination (N=104) | 83 titers |
| H1N1 Vaccine | Maternal Geometric Mean Titers (GMT) of Antibodies HAI | Post second vaccination (N=94) | 81 titers |
| H1N1 Vaccine | Maternal Geometric Mean Titers (GMT) of Antibodies HAI | At delivery (N=102) | 50 titers |
| H1N1 Vaccine | Maternal Geometric Mean Titers (GMT) of Antibodies HAI | At 3 months post delivery (N=92) | 36 titers |
| H1N1 Vaccine | Maternal Geometric Mean Titers (GMT) of Antibodies HAI | At 6 months post delivery (N=58) | 38 titers |
Secondary
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.
Time frame: Measured at birth (via cord blood) and at 3 months and 6 months of age
Population: The population consists of infants born to eligible women with nonmissing HAI titers, who had not delivered before the evaluation post second dose, and received two doses of vaccine. The N for analyses at birth, 3 and 6 months were 96, 87 and 52, respectively. Cord blood was used when available. Only some infants had a clinic visit at 6 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| H1N1 Vaccine | Percent of Infants With an HAI Titer of >= 40 | % infants with titers >= 1:40 at birth (N=96) | 64.6 Percent of participants |
| H1N1 Vaccine | Percent of Infants With an HAI Titer of >= 40 | % infants with titers >= 1:40 at 3 months (N=87) | 23.0 Percent of participants |
| H1N1 Vaccine | Percent of Infants With an HAI Titer of >= 40 | % infants with titers >= 1:40 at 6 months (N=52) | 11.5 Percent of participants |
Secondary
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.
Time frame: Measured at delivery of the baby, and at 3 months and 6 months after delivery
Population: The population consists of eligible pregnant women with nonmissing HAI titers, who had not delivered before the evaluation post second dose, and received two doses of vaccine. The N for the analyses of HAI titers at delivery, and at 3 and 6 months after were 102, 92 and 58, respectively. Only some women had a clinic visit at 6 months post delivery.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| H1N1 Vaccine | Percent of Pregnant Women With an HAI Titer of >= 40 at Delivery, 3 Months and 6 Months After Delivery | % with titers >= 1:40 at delivery (N=102) | 65.7 Percent of participants |
| H1N1 Vaccine | Percent of Pregnant Women With an HAI Titer of >= 40 at Delivery, 3 Months and 6 Months After Delivery | % with titers >= 1:40 at 3 mo post delivery (N=92) | 55.4 Percent of participants |
| H1N1 Vaccine | Percent of Pregnant Women With an HAI Titer of >= 40 at Delivery, 3 Months and 6 Months After Delivery | % with titers >= 1:40 at 6 mo post delivery (N=58) | 60.3 Percent of participants |
Secondary
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.
Time frame: Measured at entry
Population: Pregnant women who received the first H1N1 immunization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| H1N1 Vaccine | Response to Seasonal Trivalent Influenza Vaccine (TIV) | 20 titer |