Safety of and Immune Response to an H1N1 Influenza Virus Vaccine in HIV Infected Children and Youth

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Study to Assess the Safety and Immunogenicity of an Inactivated Swine-Origin H1N1 Influenza Vaccine in HIV-1 Perinatally Infected Children and Youth

Conditions
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HIV Infections, H1N1 Influenza Virus

Intervention / Treatment
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* Biological: Influenza A (H1N1) 2009 monovalent vaccine


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria for Step II: Has received a nonlicensed agent (vaccine, drug, biologic, device, blood product, or medication), other than from participation in this study, since Dose #1 or expects to receive another nonlicensed agent before the end of the study Use of anti-cancer chemotherapy or radiation therapy since 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 steroids (at least 2 mg/kg per day or at least 20 mg total dose) for more than 2 weeks since vaccine Dose #1 or high-dose inhaled steroids (more than 800 mcg/day of beclomethasone dipropionate or equivalent) since Dose #1 (nasal and topical steroids are allowed) Has received immunoglobulin or other blood products since Dose #1 Any Grade 3 toxicity or adverse event (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 study vaccine Any Grade 4 injection site reactions or fever experienced by a participant, 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 New occurrence or new awareness of Guillain-Barre syndrome in the participant or participant's family (parents, siblings, half-siblings, or children) since Dose #1 New onset of a neurological disorder including (but not limited to) absent ankle and patellar deep tendon reflexes in both legs (all four absent) since Dose #1 Disproportionate loss of strength in lower extremity or extremities compared to the upper extremities (not thought to be related to pregnancy) since Dose #1 Documented infection with 2009 Influenza A (H1N1) since Dose #1 Refusal of further vaccination by participant, parent, or guardian Development of any new disease that the investigator judges to be clinically significant or clinically significant findings since Dose #1 that, in the investigator's opinion, would compromise the safety of the subject Withdrawal of consent. Consent may be withdrawn at any time and for any reason, without penalty.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

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: Influenza A (H1N1) 2009 monovalent vaccine<br>All participants received two doses of the H1N1 influenza virus vaccine, administered 21 days apart. | Biological: Influenza A (H1N1) 2009 monovalent vaccine<br>* Two doses of vaccine, delivered 21 days apart, with each dose consisting of two 15-microgram intramuscular injections<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. 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. | Measured up to 7 months after vaccination | 
| 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 7 months after vaccination | 
| 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 | 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 10 days after second dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With an HAI Titer >=40 at Long-term Follow-up |  | Measured at 6 months after second dose | 
| Geometric Mean Antibody Titers (GMT) HAI | Presents the value of the geometric mean titer at each time point. | Measured after first and second doses and 6 months after second dose | 
| 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. | Measured at entry, 21 days after first dose, and 10 days after second dose | 
| 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. | Measured at entry, 21 days after first dose, and 10 days and 6 months after second dose | 
| 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. | Measured at entry, 21 days after first dose, and 10 days after second dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza A Virus, H1N1 Subtype, Vaccine, Children, Adolescents, HIV-Infected, Perinatal HIV Infection, Treatment experienced