Clinical trial NCT00992836: Safety of and Immune Response to an H1N1 Influenza Virus Vaccine in HIV Infected Children and Youth
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
H1N1 Influenza Virus
Keywords: Influenza A Virus, H1N1 Subtype
Vaccine
Children
Adolescents
HIV-Infected
Perinatal HIV Infection
Treatment experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2009-10-09
Enrollment: 155
Sex: ALL
Minimum age (years): 4
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Number of Participants Who Had at Least One Adverse Event (AE)
timeFrame: Measured up to 7 months after vaccination
measure: The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine
timeFrame: Measured up to 7 months after vaccination
measure: Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose
timeFrame: Measured at Day 21
measure: Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40
timeFrame: Measured at 21 days after first dose and 10 days after second dose
Secondary outcomes:
measure: Percent of Participants With an HAI Titer >=40 at Long-term Follow-up
timeFrame: Measured at 6 months after second dose
measure: Geometric Mean Antibody Titers (GMT) HAI
timeFrame: Measured after first and second doses and 6 months after second dose
measure: Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values
timeFrame: Measured at entry, 21 days after first dose, and 10 days after second dose
measure: HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV)
timeFrame: Measured at entry, 21 days after first dose, and 10 days and 6 months after second dose
measure: Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens
timeFrame: Measured at entry, 21 days after first dose, and 10 days after second dose
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Pediatric Infectious Diseases CRS
state: Alabama
city: Alhambra
country: United States
facility: Usc La Nichd Crs
state: California
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Los Angeles
country: United States
facility: UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
state: California
city: San Francisco
country: United States
facility: Univ. of California San Francisco NICHD CRS
state: California
city: Torrance
country: United States
facility: Harbor UCLA Medical Ctr. NICHD CRS
state: California
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS
state: Colorado
city: Washington
country: United States
facility: Children's National Med. Ctr. Washington DC NICHD CRS
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS
state: Florida
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit CRS
state: Florida
city: Tampa
country: United States
facility: USF - Tampa NICHD CRS
state: Florida
city: Chicago
country: United States
facility: Rush Univ. Cook County Hosp. Chicago NICHD CRS
state: Illinois
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS
state: Illinois
city: Baltimore
country: United States
facility: Univ. of Maryland Baltimore NICHD CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Boston
country: United States
facility: Children's Hosp. of Boston NICHD CRS
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS
state: Massachusetts
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan NICHD CRS
state: Michigan
city: Newark
country: United States
facility: Rutgers - New Jersey Medical School CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx-Lebanon CRS
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Metropolitan Hosp. NICHD CRS
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: Rochester
country: United States
facility: Strong Memorial Hospital Rochester NY NICHD CRS
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS
state: New York
city: Durham
country: United States
facility: DUMC Ped. CRS
state: North Carolina
city: Philadelphia
country: United States
facility: The Children's Hosp. of Philadelphia IMPAACT CRS
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital CRS
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Research Institute CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Pediatric HIV/AIDS Research Program CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Pat Flynn, MD
role: STUDY_CHAIR
References:
citation: Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team; Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, Garten RJ, Gubareva LV, Xu X, Bridges CB, Uyeki TM. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009 Jun 18;360(25):2605-15. doi: 10.1056/NEJMoa0903810. Epub 2009 May 7.
citation: Gelinck LB, van den Bemt BJ, Marijt WA, van der Bijl AE, Visser LG, Cats HA, Rimmelzwaan GF, Kroon FP. Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible. Vaccine. 2009 Apr 21;27(18):2469-74. doi: 10.1016/j.vaccine.2009.02.053. Epub 2009 Feb 24.
citation: Flynn P, Nachman S, Spector SA, Cunningham CK, Weinberg A, Pass R, Muresan P, Levy W, Siberry G, Handelsman E for the IMPAACT P1088 and P1089 Teams: Safety and Immunogenicity of 2009 H1N1 Influenza Immunization in HIV-1 Perinatally Infected Children and Youth. Presented at the IDSA conference, October 2010.
citation: Flynn PM, Nachman S, Spector SA, Cunningham CK, Weinberg A, Pass R, Muresan P, Levy W, Petzold E, Heckman B, Siberry G, Handelsman E for the IMPAACT P1088 and P1089 Teams. 2009 Influenza A (H1N1) Immunization in HIV-1 Perinatally Infected Children and Youth. Presented at the Retroviruses Conference, Feb 2010.
citation: Curtis DJ, Muresan P, Nachman S, Fenton T, Richardson KM, Dominguez T, Flynn PM, Spector SA, Cunningham CK, Bloom A, Weinberg A. Characterization of functional antibody and memory B-cell responses to pH1N1 monovalent vaccine in HIV-infected children and youth. PLoS One. 2015 Mar 18;10(3):e0118567. doi: 10.1371/journal.pone.0118567. eCollection 2015.
citation: Flynn PM, Nachman S, Muresan P, Fenton T, Spector SA, Cunningham CK, Pass R, Yogev R, Burchett S, Heckman B, Bloom A, Utech LJ, Anthony P, Petzold E, Levy W, Siberry GK, Ebiasah R, Miller J, Handelsman E, Weinberg A; IMPAACT P1088 Team. Safety and immunogenicity of 2009 pandemic H1N1 influenza vaccination in perinatally HIV-1-infected children, adolescents, and young adults. J Infect Dis. 2012 Aug 1;206(3):421-30. doi: 10.1093/infdis/jis360. Epub 2012 May 21.