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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00992836
• Other study ID #: P1088
• Secondary ID: 10840IMPAACT P10
• Status: Completed
• Phase: Phase 2
• Start date: October 2009
• Est. completion date: August 2010

Study information

• Verified date: December 2014
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: August 2010
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• H1N1 Influenza Virus
• HIV Infections
• Influenza, Human

Intervention

Biological:
• Influenza A (H1N1) 2009 monovalent vaccine
Two doses of vaccine, delivered 21 days apart, with each dose consisting of two 15-microgram intramuscular injections

Locations

Country	Name	City	State
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
Puerto Rico	University of Puerto Rico Pediatric HIV/AIDS Research Program CRS	San Juan
United States	Usc La Nichd Crs	Alhambra	California
United States	Univ. of Colorado Denver NICHD CRS	Aurora	Colorado
United States	Johns Hopkins Univ. Baltimore NICHD CRS	Baltimore	Maryland
United States	Univ. of Maryland Baltimore NICHD CRS	Baltimore	Maryland
United States	UAB Pediatric Infectious Diseases CRS	Birmingham	Alabama
United States	Boston Medical Center Ped. HIV Program NICHD CRS	Boston	Massachusetts
United States	Children's Hosp. of Boston NICHD CRS	Boston	Massachusetts
United States	Bronx-Lebanon CRS	Bronx	New York
United States	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York
United States	Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS	Chicago	Illinois
United States	Rush Univ. Cook County Hosp. Chicago NICHD CRS	Chicago	Illinois
United States	Children's Hospital of Michigan NICHD CRS	Detroit	Michigan
United States	DUMC Ped. CRS	Durham	North Carolina
United States	South Florida CDTC Ft Lauderdale NICHD CRS	Fort Lauderdale	Florida
United States	Texas Children's Hospital CRS	Houston	Texas
United States	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida
United States	University of California, UC San Diego CRS	La Jolla	California
United States	Miller Children's Hosp. Long Beach CA NICHD CRS	Long Beach	California
United States	UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS	Los Angeles	California
United States	St. Jude Children's Research Hospital CRS	Memphis	Tennessee
United States	Pediatric Perinatal HIV Clinical Trials Unit CRS	Miami	Florida
United States	Columbia IMPAACT CRS	New York	New York
United States	Metropolitan Hosp. NICHD CRS	New York	New York
United States	Nyu Ny Nichd Crs	New York	New York
United States	Rutgers - New Jersey Medical School CRS	Newark	New Jersey
United States	The Children's Hosp. of Philadelphia IMPAACT CRS	Philadelphia	Pennsylvania
United States	Strong Memorial Hospital Rochester NY NICHD CRS	Rochester	New York
United States	Univ. of California San Francisco NICHD CRS	San Francisco	California
United States	Seattle Children's Research Institute CRS	Seattle	Washington
United States	SUNY Stony Brook NICHD CRS	Stony Brook	New York
United States	USF - Tampa NICHD CRS	Tampa	Florida
United States	Harbor UCLA Medical Ctr. NICHD CRS	Torrance	California
United States	Children's National Med. Ctr. Washington DC NICHD CRS	Washington	District of Columbia
United States	Howard Univ. Washington DC NICHD CRS	Washington	District of Columbia
United States	WNE Maternal Pediatric Adolescent AIDS CRS	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (4)

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 Y

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 You

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. — View 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. Erratum in: N Engl J Med. 2009 Jul 2;361(1):102. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Measured up to 7 months after vaccination
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.	Measured up to 7 months after vaccination
Primary	Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose		Measured at Day 21
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.	Measured at 21 days after first dose and 10 days after second dose
Secondary	Percent of Participants With an HAI Titer >=40 at Long-term Follow-up		Measured at 6 months after second dose
Secondary	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
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.	Measured at entry, 21 days after first dose, and 10 days after second dose
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.	Measured at entry, 21 days after first dose, and 10 days and 6 months after second dose
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.	Measured at entry, 21 days after first dose, and 10 days after second dose

External Links

•   Click here for information on the IMPAACT group and for the package insert on the H1N1 vaccine.
•   Click here for the table used for grading toxicities: DAIDS Grading Severity of AEs, V1.0, Dec04.