H1N1 Influenza Virus, HIV Infections
Conditions
Keywords
Influenza A Virus, H1N1 Subtype, Vaccine, Children, Adolescents, HIV-Infected, Perinatal HIV Infection, Treatment experienced
Brief summary
Children and people infected with HIV are particularly susceptible to influenza infections. This study testED the safety and effectiveness of a vaccine for the new H1N1 influenza virus in children and youth infected with HIV.
Detailed description
The new H1N1 influenza virus seen in 2009 has been designated a pandemic by the World Health Organization, due to the sustained community outbreaks seen in the United States and Mexico. Based on preliminary data, it appears children and young adults were particularly at risk of the H1N1 virus. People infected with HIV were also more susceptible to severe influenza infections than those who are uninfected. Children with HIV infection, then, have a compounded risk of H1N1 infection. Higher doses of influenza vaccines are associated with the development of higher levels of serum antibodies, which are needed to resist infection. Higher vaccine doses can be used to improve vaccine effectiveness in at-risk populations. This study tested the safety and immune response of HIV infected children and youth to a high dose of a vaccine for the new H1N1 influenza virus. Participation in this study lasted 7 months and had two steps. The first step involved receiving the first dose of H1N1 virus vaccine, and the second step, occurring 21 days later, involved receiving the second dose of vaccine. Each dose of vaccine was delivered via two intramuscular shots (four total injections). After receiving each dose of the vaccine, participants were given a diary to record any symptoms or reactions. Participants were stratified into three groups by age, including 4 to 9 years, 9 to 18 years, and 18 to 25 years. Participants completed five scheduled visits, taking place at screening, study entry, Days 21 and 31, and after 7 months. Measurements taken on these visits included a medical history, physical and neurological exams, a blood draw, and, when applicable, a pregnancy test. In addition to these visits, participants received up to three additional phone calls or visits occurring 2 and 10 days after the first dose of vaccine and 2 days after the second dose of vaccine to check for reactions to the vaccine.
Interventions
Two doses of vaccine, delivered 21 days apart, with each dose consisting of two 15-microgram intramuscular injections
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
ALL
Age
4 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
for Step I: * HIV infected * HIV-1 was perinatally acquired, in the opinion of the investigator * Participants receiving antiretrovirals (ARVs) must have been receiving a stable regimen for 90 days prior to entry with no intention to modify their regimen within 60 days following study entry * Participants not receiving ARVs at entry must not have received ARVs within 90 days prior to entry and must NOT plan to initiate ARVs within 60 days following study entry * Ability to complete all study immunizations and evaluations, in the opinion of the investigator * Agrees to use contraception, if necessary * Documented platelet count of more than 50,000 per mm3 and an absolute neutrophil count (ANC) of more than 500 per mm3 within the 30 days prior to study entry * Youth of legal age (from 18 to 25 years of age), parent or legal guardian, or participants who are emancipated minors must provide informed consent Inclusion Criteria for Step II: * Received the first dose of Influenza A (H1N1) 2009 monovalent vaccine at least 21 days ago * Documented platelet count of more than 50,000 per mm3 and an ANC of more than 500 per mm3 within the 30 days prior to Step II entry * If a woman became pregnant after Dose #1, she must be at more than 14 weeks of gestation and have her obstetrician's permission to receive the vaccine
Exclusion criteria
for Step I: * Pregnancy * Known allergy to egg protein (egg or egg product) or other components in the vaccines (these may include, but are not limited to: neomycin and polymyxin) * History, in the opinion of the site investigator, of severe reactions following previous immunization with seasonal influenza vaccines that would contraindicate receipt of any influenza vaccine. * History of probable or proven pandemic 2009 Influenza A (H1N1) infection prior to study entry * Has received any live licensed vaccine within 4 weeks or inactivated licensed vaccine within 2 weeks prior to study entry * Has received a nonlicensed agent (vaccine, drug, biologic, device, blood product, or medication) within 4 weeks prior to study entry or expects to receive another nonlicensed agent during the course of the study * Has an acute illness or a documented temperature greater than or equal to 100.0 degrees Fahrenheit within 24 hours prior to study entry * Use of anti-cancer chemotherapy or radiation therapy within the 36 months preceding study entry or has immunosuppression as a result of an underlying illness or treatment (other than HIV-1 infection) * Has an active neoplastic disease * Long-term use of glucocorticoids, including oral or parenteral prednisone or equivalent (at least 2 mg/kg per day or at least 20 mg total dose) for more than 2 weeks in the past 6 months or high-dose inhaled steroids (more than 800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months. Nasal and topical steroids are allowed. * Has received immunoglobulin or other blood products within the 3 months prior to study entry * History of Guillain-Barre syndrome in the subject or subject's family, including parents, siblings, half-siblings, and children * Onset of a neurological disorder including (but not limited to) absent ankle and patellar deep tendon reflexes 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 within the past 6 months * Has 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Who Had at Least One Adverse Event (AE) | Measured up to 7 months after vaccination | Shows the number of participants who had at least one adverse event (AE) in each category. The AEs 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 7 months after vaccination | 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 Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40 | Measured at 21 days after first dose and 10 days after second dose | 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 |
|---|---|---|
| Percent of Participants With an HAI Titer >=40 at Long-term Follow-up | Measured at 6 months after second dose | — |
| Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | Measured at entry, 21 days after first dose, and 10 days after second dose | The TIV assay was not performed due to lack of available cells after completion of other planned assays. The median and interquartile range (IQR) of T-Cell ELISPOT-measured pH1N1 Granzyme B spot-forming cells (SFC)/10\^6 peripheral blood mononucleated cell (PBMC). The median and interquartile range (IQR) of T-Cell ELISPOT-measured PHA INFgamma spot-forming cells (SFC)/10\^6 PBMC. The median and interquartile range (IQR) of T-Cell ELISPOT-measured PHA Granzyme B spot-forming cells (SFC)/10\^6 PBMC. |
| Geometric Mean Antibody Titers (GMT) HAI | Measured after first and second doses and 6 months after second dose | Presents the value of the geometric mean titer at each time point. |
| Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | Measured at entry, 21 days after first dose, and 10 days after second dose | The median and interquartile range (IQR) of B-Cell ELISPOT-measured IgG antibody-secreting cells (ASC)/10\^6 peripheral blood mononucleated cell (PBMC) and the median and interquartile range (IQR) of T-Cell ELISPOT-measured pH1N1 IFNgamma spot-forming cells (SFC)/10\^6 PBMC. |
| HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV) | Measured at entry, 21 days after first dose, and 10 days and 6 months after second dose | 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. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled from 37 sites between October 14, 2009 and November 12, 2009. Participants were stratified by age in three groups: \>=4 to \< 9 years old, \>=9 to \< 18 years old and \>=18 to \<25 years old.
Pre-assignment details
One study participant was inadvertently enrolled with acute illness, was not given any vaccination and was immediately taken off study. A second study participant received the first vaccination but it was discovered that he/she was not compliant with the ARV regimen and was taken off study before receiving the second dose of vaccine.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants received two doses of the H1N1 influenza virus vaccine, administered 21 days apart. Each dose consisted of two 15-microgram intramuscular injections. | 155 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 13 years STANDARD_DEVIATION 6 |
| Age Strata >=18 to < 25 years old | 50 Participants |
| Age Strata >=4 to < 9 years old | 54 Participants |
| Age Strata >=9 to < 18 years old | 51 Participants |
| CD4 Cells Count | 568 cells / mm^3 STANDARD_DEVIATION 242 |
| Percentage of CD4 Cells | 29 percentage STANDARD_DEVIATION 11 |
| Region of Enrollment Puerto Rico | 8 participants |
| Region of Enrollment United States | 147 participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 113 / 155 |
| serious Total, serious adverse events | 6 / 155 |
Outcome results
Primary
Percent of Participants With a Hemagglutinin 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 10 days after second dose
Population: The HAI titers following the first vaccination were summarized for the eligible study participants who received at least one vaccine and had nonmissing HAI data, and the titers following the second vaccination for the eligible study participants who received both doses of vaccine and had nonmissing HAI data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Study Participants | Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40 | Post dose 1 (N=140) | 72.1 percentage of participants |
| All Study Participants | Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40 | Post dose 2 (N=142) | 82.4 percentage 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. The AEs 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 7 months after vaccination
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Study Participants | The Number of Participants Who Had at Least One Adverse Event (AE) | Overall (New AEs after start of treatment) | 113 participants |
| All Study Participants | The Number of Participants Who Had at Least One Adverse Event (AE) | Grade 4 AEs (New, after start of treatment) | 0 participants |
| All Study Participants | The Number of Participants Who Had at Least One Adverse Event (AE) | Grade 3 AEs (New, after start of treatment) | 7 participants |
| All Study Participants | The Number of Participants Who Had at Least One Adverse Event (AE) | Grade 2 local and systemic AEs to injection | 6 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 7 months after vaccination
Population: The 154 study participants who received at last one vaccination are included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine | 7 participants |
Primary
Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose
Time frame: Measured at Day 21
Population: The 154 study participants who received at last one vaccination are included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose | 0 participants |
Secondary
Cell-mediated Immune Responses, 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 peripheral blood mononucleated cell (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, 21 days after first dose, and 10 days after second dose
Population: The participants who had received all doses of vaccine up to that timepoint and had sufficient samples for testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Study Participants | Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | IgG ASC/10^6 PBMC, Week 0 (N=46) | 6 ASC or SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | IgG ASC/10^6 PBMC, Post Dose 1 (N=40) | 13 ASC or SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | IgG ASC/10^6 PBMC, Post Dose 2 (N=40) | 12 ASC or SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | pH1N1 IFNgamma SFC/10^6 PBMC, Week 0 (N=68) | 317 ASC or SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | pH1N1 IFNgamma SFC/10^6 PBMC, Post Dose 1 (N=68) | 363 ASC or SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values | pH1N1 IFNgamma SFC/10^6 PBMC, Post Dose 2 (N=65) | 261 ASC or SFC/10^6 PBMC |
Secondary
Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens
The TIV assay was not performed due to lack of available cells after completion of other planned assays. The median and interquartile range (IQR) of T-Cell ELISPOT-measured pH1N1 Granzyme B spot-forming cells (SFC)/10\^6 peripheral blood mononucleated cell (PBMC). The median and interquartile range (IQR) of T-Cell ELISPOT-measured PHA INFgamma spot-forming cells (SFC)/10\^6 PBMC. The median and interquartile range (IQR) of T-Cell ELISPOT-measured PHA Granzyme B spot-forming cells (SFC)/10\^6 PBMC.
Time frame: Measured at entry, 21 days after first dose, and 10 days after second dose
Population: The participants who had received all doses of vaccine up to that timepoint and had sufficient samples for testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | pH1N1 Granzyme B SFC/10^6 PBMC, Week 0 (N=64) | 35 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | pH1N1 Granzyme B SFC/10^6 PBMC, Week 3 (N=62) | 26 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | pH1N1 Granzyme B SFC/10^6 PBMC, Week 5 (N=61) | 30 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | PHA INFgamma SFC/10^6 PBMC, Week 0 (N=68) | 699 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | PHA INFgamma SFC/10^6 PBMC, Week 3 (N=68) | 637 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | PHA INFgamma SFC/10^6 PBMC, Week 5 (N=65) | 624 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | PHA Granzyme B SFC/10^6 PBMC, Week 0 (N=64) | 3250 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | PHA Granzyme B SFC/10^6 PBMC, Week 3 (N=62) | 3340 SFC/10^6 PBMC |
| All Study Participants | Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens | PHA Granzyme B SFC/10^6 PBMC, Week 5 (N=60) | 2045 SFC/10^6 PBMC |
Secondary
Geometric Mean Antibody Titers (GMT) HAI
Presents the value of the geometric mean titer at each time point.
Time frame: Measured after first and second doses and 6 months after second dose
Population: The HAI titers following the first vaccination were summarized for the eligible study participants who received at least one vaccine and had nonmissing HAI data, and the titers following the second vaccination for the eligible study participants who received both doses of vaccine and had nonmissing HAI data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Study Participants | Geometric Mean Antibody Titers (GMT) HAI | At 21 days after the first vaccination (N=140) | 85 titers |
| All Study Participants | Geometric Mean Antibody Titers (GMT) HAI | At 10 days after the second vaccination (N=142) | 127 titers |
| All Study Participants | Geometric Mean Antibody Titers (GMT) HAI | At 6 months after the second vaccination (N=138) | 33 titers |
Secondary
HAI Titers Against Seasonal Influenza Viruses Containing 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, 21 days after first dose, and 10 days and 6 months after second dose
Population: The participants who had received all doses of vaccine up to that timepoint and had sufficient samples for testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Study Participants | HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV) | Post Dose 1 (N=121) | 40 titer |
| All Study Participants | HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV) | Week 0 (N=123) | 40 titer |
| All Study Participants | HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV) | Post Dose 2 (N=121) | 40 titer |
| All Study Participants | HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV) | 6 months Post Dose 2 (N=122) | 40 titer |
Secondary
Percent of Participants With an HAI Titer >=40 at Long-term Follow-up
Time frame: Measured at 6 months after second dose
Population: The HAI titers were summarized for the eligible study participants who received both doses of vaccine and had nonmissing HAI data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | Percent of Participants With an HAI Titer >=40 at Long-term Follow-up | 57.2 percentage of participants |