Clinical trial NCT00459316: Safety of and Immune Response to a Meningitis Vaccine in HIV-Infected Children and Youth
Official title: Phase I/II Study of Safety and Immunogenicity of Quadrivalent Meningococcal Conjugate Vaccine (MCV4) in HIV-Infected Children and Youth And Open Label Immunogenicity Study of a Booster Dose of MCV4 in Previously Immunized HIV-Infected Children and Youth
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Meningitis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
First posted: 2007-04-11
Enrollment: 384
Sex: ALL
Minimum age (years): 2
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Bacterial meningitis infection is common in youth 2 to 24 years of age in the United States. This disease can be treated by antibiotics, but mortality rates associated with meningitis of up to 53% have been estimated. Vaccination against meningitis may be effective in preventing this disease, especially for HIV-infected youth who have weakened immune systems. The purpose of this study was to determine the safety of and immune response to a preventive meningitis vaccine in HIV-infected youth.

Detailed description: In the United States, youth 2 to 24 years of age are at high risk for bacterial meningitis infection. Despite antibiotic treatment, the mortality rate for meningitis and sepsis can reach as high as 53% caused by Neisseria meningitidis. This rate could be higher in immunocompromised individuals, such as those infected with HIV. To prevent infection, vaccination against meningitis is recommended by the CDC at ages 11, 15, and 18. The quadrivalent meningococcal conjugate vaccine (MCV4) is a vaccine that has been observed to elicit an appropriate immune response to N. meningitidis and was approved by the FDA in January 2005. However, to date, no studies have been done to determine the safety and immunogenicity of this vaccine in HIV-infected individuals. The purpose of this study was to determine the safety and immunogenicity of MCV4 in HIV-infected youth 2 to 24 years of age.

The study was originally designed for participants to be followed for 72 weeks. Participants were enrolled in three groups by age and CD4% as follows:

Group 1: Age 11 to 24 years, CD4% of 15% or higher. Enrollment was further stratified by CD4%: 15% to \<25%, and \>= 25%.

Group 2: Age 11 to 24 years, CD4% \< 15%.

Group 3: Age 2 to 10 years, CD4% of 25% or higher.

At study entry, all study participants received one injection of MCV4 (Step 1). Participants were observed for 30 minutes post-injection to monitor for adverse events. A clinic visit was required 24 hours post-injection if the participant reported adverse events. At Week 24, participants in Group 1 who did not experience any disqualifying adverse events after the first injection were randomly assigned to receive a second injection of MCV4 or no further injections. Group 2, and Group 3 participants who had no disqualifying adverse events after the first injection received a second injection of MCV4 at Week 24 (Step 2).

There were five study visits in Steps 1 and 2; they occurred at study entry and at Weeks 4, 24, 28, and 72. At these visits, a physical exam, assessment of HIV-related symptoms, and blood collection occurred. In addition, study participants were contacted by telephone at Days 3 and 7 and Weeks 1, 6, and 25 after the first vaccination. Participants in Groups 1B and 2 who received a second injection were contacted by telephone at Weeks 30 and 48.

As of November 2010, due to data from this study (P1065) and recommendations from the Advisory Committee for Immunization Practices (ACIP) of the Center for Disease Control (CDC), eligible participants in Groups 1 (1A and 1B) and 3 of P1065 received a booster dose of MCV4 at approximately 3.5 years (+/- 6 months) after the initial MCV4 vaccination. Participants were then observed for 30 minutes post-injection to monitor for adverse events. Participants were also observed at Week 1 for vaccine adverse reactions.

This portion of the study (Step 3) lasted an additional 24 weeks. There were 4 study visits; they occurred at entry, at Days 7-8, and at Weeks 4 and 24. At these visits, a physical exam, assessment of HIV-related symptoms, and blood collection occurred. The purpose of this follow-up study was to determine the safety and immunogenicity of a MCV4 booster dose in HIV-infected participants who have previously received one or two MCV4 vaccinations on this study.

Eligibility criteria: Inclusion Criteria for Steps 1, 2, and 3:

* HIV-infected
* Age greater than or equal to 2 and less than 25 years (Steps 1 and 2 only)
* CD4% documented within 120 days of study entry
* Participants on antiretroviral therapy (ART) must have been on stable ART regimen for at least 90 days prior to study entry
* Able and willing to complete all study immunizations and evaluations
* Parent or guardian willing to provide informed consent, if applicable
* Participants and/or their partners who are sexually active had to agree to use at least one of the following methods of contraception as long as they are on the study: hormonal birth control drugs (oral, injectable or transdermal); male or female condoms with or without a spermicide; diaphragm/cervical cap with spermicide; intrauterine device (IUD)

Inclusion Criteria specific to Step 3:

* Participants must have been enrolled in Groups 1 or 3 of previous versions of P1065
* Participants did not have to be less than 25 years of age
* Participants must have had serology data from Weeks 0, 4, and 28 from their previous participation in P1065
* Participants must have been within 3.5 years +/- 6 months from the first MCV4 dose received in a previous version of P1065

Exclusion Criteria for Step 1:

* Any nonstudy vaccine on study entry day
* Any inactive vaccine within 2 weeks prior to study entry
* Plans to receive any vaccine 2 weeks after the first injection
* Receipt of any live nonstudy vaccine within 4 weeks prior to study entry
* Meningococcal conjugate vaccine at any time prior to study entry
* Meningococcal polysaccharide vaccine within 2 years prior to study entry
* Known hypersensitivity to any component of the MCV4 vaccine, including diphtheria toxoid
* Known hypersensitivity to dry natural rubber latex
* Life-threatening reaction after previous administration of a vaccine containing similar components
* Family history or personal history of Guillain-Barre Syndrome (GBS)
* Clinically significant diseases that, in the investigator's opinion, would interfere with the study
* Current immunomodulatory therapy, including IL-2, any interferon product, GM-CSF, or thalidomide. Participants taking G-CSF or erythropoietin were not excluded.
* Current immunosuppressive therapy, including equivalent of 1 mg/kg/per day or more of prednisone 2 weeks prior to study entry OR planned corticosteroid therapy lasting 2 weeks or longer. Participants using nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded.
* Cancer within 12 weeks of study entry
* Cancer treatment currently or within 12 weeks of study entry
* Loss of strength in lower extremity within 24 weeks prior to study entry
* Bleeding disorder or anticoagulant therapy prior to study entry
* Absence of ankle and patellar deep tendon reflexes (DTRs) (all four)
* Recent receipt of IGIV or any blood or immunoglobulin product (except washed blood cells). More information about this criterion can be found in the protocol.
* Other acute or chronic medical or surgical conditions or contraindications that, in the opinion of the investigator, might have interfered with the study
* Any new and unresolved Grade 3 or higher laboratory toxicity within 120 days prior to study entry
* Any new and unresolved Grade 3 or higher clinical toxicity within 120 days prior to study entry
* Pregnancy or breastfeeding

Exclusion Criteria for Step 2:

* New occurrence or awareness of GBS in the participant or participant's family since study entry
* Loss of strength in lower extremity or extremities since first vaccination
* Absence of ankle and patellar DTRs (all four)
* New diagnosis of active cancer, or chemotherapy treatment of an established cancer diagnosis since study entry
* Any Grade 4 toxicity since last vaccination. Participants who experience toxicities unrelated to the vaccine are not excluded.
* Change in ART in the 90 days prior to second vaccination
* Certain Grade 3 toxicities. More information on this criterion can be found in the protocol.
* Treatment with immunosuppressive or immunomodulation therapy (other than corticosteroids) within 60 days of planned second vaccination
* Severe allergic reaction requiring medical intervention within 24 hours of the first vaccination
* New diagnosis of any coagulation disorder that would contraindicate intramuscular injection
* Toxicity from first vaccination. More information on this criterion can be found in the protocol.
* Any new diseases that the investigator judges to be clinically significant OR clinically significant findings since the first vaccination that, in the opinion of the investigator, would interfere with the study
* Any new clinical Grade 3 or higher toxicity that has not resolved within 2 weeks prior to planned second vaccination
* Pregnancy or breastfeeding. Pregnant or breastfeeding participants were to be followed to pregnancy outcome.

Exclusion Criteria for Step 3:

* Receipt of any dose of non-study meningococcal vaccine since initial enrollment into P1065
* New occurrence or new awareness of GBS in the participant or participant's family since the last P1065 study visit
* Loss of strength in lower extremity or extremities since the last MCV4 vaccination
* Absence of ankle and patellar Deep Tendon Reflexes (DTRs) (all 4)
* New diagnosis of an active malignancy, or chemotherapy treatment of an established diagnosis since the last P1065 study visit
* New diagnosis or suspected disease of the immune system since the last P1065 study visit
* Participant or legal guardian refuses further vaccine
* Participant requiring treatment with medications that were disallowed while on this study (see protocol)
* Grade 3 or higher toxicities (for example, Grade 3 seizure or allergic reaction) secondary to receipt of vaccine in previous version of P1065 meriting vaccine discontinuation, as determined by the IMPAACT P1065 Protocol Team and the site principal investigator
* Current immunomodulatory therapy, including IL-2, any interferon product, GM-CSF, or thalidomide \[Note: G-CSF and erythropoietin are allowed\]
* Current immunosuppressive therapy, including the equivalent of greater than or equal to 1 mg/kg/per day of prednisone in the 2 weeks preceding study entry
* Participants for whom long-term corticosteroid therapy (greater than or equal to 2 weeks) was anticipated were excluded \[Note: non-steroidal anti-inflammatory agents and inhaled, intranasal and topical corticosteroids were allowed\]
* A severe allergic reaction (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) that required medical intervention, occurring within 24 hours of the first vaccine and potentially attributable to that first vaccine
* New diagnosis of any coagulation disorder that would contraindicate IM injections since the last P1065 study visit
* Breastfeeding
* Any new diseases which the investigators judged to be clinically significant (other than HIV infection) or clinically significant findings since enrollment into P1065 that, in the investigators' opinion, would have compromise the outcome of this study
* Any new greater than or equal to grade 3 clinical toxicity that is not related to vaccine and had not resolved within 2 weeks before entry into Step 3

Primary outcomes:
measure: Number of Immunogenic Responders, With Response Defined as a 4-fold or Greater Increase in Serum Bactericidal Antibody Titers From Study Entry to Week 28 After 2 Doses of MCV-4.
timeFrame: Study entry and Week 28
measure: Number of Participants With Short-term Immunogenicity, Defined as Number of Seroconverters at Week 4 (Those With at Least a 4-fold Rise in Meningococcal Serum Bactericidal Titers From Baseline)
timeFrame: At Study entry, Week 4
measure: Long-term Immunogenicity, as Assessed by Number of Participants With Protective Levels of Antibody at Week 72
timeFrame: Week 72
measure: Number of Participants With Grade 3 or Higher Adverse Events Within 42 Days Following Dose 1 of the Vaccine.
timeFrame: From administration of Dose 1 at week 0 to 42 days post-vaccination
measure: Number of Participants With Reactions and Grade 3 or Higher Adverse Events Within 42 Days Following Dose 2 of the Vaccine.
timeFrame: From administration of Dose 2 at week 24 to 6 weeks post-vaccination
measure: Number of Participants With Immunogenicity at Step 3 Entry
timeFrame: At 3.5 years (Step 3 entry)
measure: Number of Participants With 4-fold Memory Response in Step 3
timeFrame: Step 3 entry and Week 1 post-booster vaccine
measure: Number of Participants With Seropositive Memory Response (in Step 3)
timeFrame: Step 3 entry and Week 1 post-booster vaccine
measure: Number of Participants With Primary Response (in Step 3)
timeFrame: Step 3 entry and Week 4 post-booster vaccine
measure: Number of Participants With Immunogenicity at Step 3 Weeks 4 and 24
timeFrame: At Step 3 Weeks 4 and 24 post-booster vaccine
Secondary outcomes:
measure: Immunogenic Response to Serogroup C in Group 2
timeFrame: At Weeks 4, 28, and 72
measure: Number of Participants With Protective Antibody Titers for Serogroup C at Step 3 Entry
timeFrame: At 3.5 years
measure: Immunologic Memory for Serogroup C by Treatment Arm (1 vs. 2 Doses)
timeFrame: At Week 1 post-booster vaccination
measure: Immunologic Memory or Primary Response for Serogroup C by Treatment Arm
timeFrame: At Week 4 post-booster vaccination
measure: Safety, as Assessed by Number of Participants With Reactions and Grade 3 or Higher Adverse Events Within 42 Days Following Step 3 Dose of the Vaccine.
timeFrame: From administration of vaccination at Step 3 entry through 6 weeks post-vaccination
Other outcomes:
Locations:
city: Alhambra
country: United States
facility: Usc La Nichd 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: Children's Hospital of Los Angeles NICHD CRS
state: California
city: Los Angeles
country: United States
facility: UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
state: California
city: San Diego
country: United States
facility: University of California, UC San Diego 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: New Orleans
country: United States
facility: Tulane Univ. New Orleans NICHD CRS
state: Louisiana
city: Baltimore
country: United States
facility: Univ. of Maryland 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: Pediatric, Adolescent, and Maternal AIDS (PAMA) Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
name: George K. Siberry, MD, MPH
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, Department of Pediatrics, University of South Florida College of Medicine
name: Jorge Lujan-Zilbermann, MD, MS
role: STUDY_CHAIR
References:
citation: Campos-Outcalt D. Meningococcal vaccine: New product, new recommendations. J Fam Pract. 2005 Apr;54(4):324-6.
citation: Centers for Disease Control and Prevention (CDC). Update: Guillain-Barre syndrome among recipients of Menactra meningococcal conjugate vaccine--United States, June 2005-September 2006. MMWR Morb Mortal Wkly Rep. 2006 Oct 20;55(41):1120-4.
citation: Keyserling H, Papa T, Koranyi K, Ryall R, Bassily E, Bybel MJ, Sullivan K, Gilmet G, Reinhardt A. Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med. 2005 Oct;159(10):907-13. doi: 10.1001/archpedi.159.10.907.
citation: Mehlhorn AJ, Balcer HE, Sucher BJ. Update on prevention of meningococcal disease: focus on tetravalent meningococcal conjugate vaccine. Ann Pharmacother. 2006 Apr;40(4):666-73. doi: 10.1345/aph.1G486. Epub 2006 Mar 7.
citation: Platonov AE, Vershinina IV, Kuijper EJ, Borrow R, Kayhty H. Long term effects of vaccination of patients deficient in a late complement component with a tetravalent meningococcal polysaccharide vaccine. Vaccine. 2003 Oct 1;21(27-30):4437-47. doi: 10.1016/s0264-410x(03)00440-7.
citation: Pearson IC, Baker R, Sullivan AK, Nelson MR, Gazzard BG. Meningococcal infection in patients with the human immunodeficiency virus and acquired immunodeficiency syndrome. Int J STD AIDS. 2001 Jun;12(6):410-1. doi: 10.1258/0956462011923237.
citation: Siberry GK, Williams PL, Lujan-Zilbermann J, Warshaw MG, Spector SA, Decker MD, Heckman BE, Demske EF, Read JS, Jean-Philippe P, Kabat W, Nachman S; IMPAACT P1065 Protocol Team. Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents. Pediatr Infect Dis J. 2010 May;29(5):391-6. doi: 10.1097/INF.0b013e3181c38f3b.
citation: Spector SA, Qin M, Lujan-Zilbermann J, Singh KK, Warshaw MG, Williams PL, Jean-Philippe P, Fenton T, Siberry GK; IMPAACT P1065 Protocol Team. Genetic variants in toll-like receptor 2 (TLR2), TLR4, TLR9, and FCgamma receptor II are associated with antibody response to quadrivalent meningococcal conjugate vaccine in HIV-infected youth. Clin Vaccine Immunol. 2013 Jun;20(6):900-6. doi: 10.1128/CVI.00042-13. Epub 2013 Apr 17.
citation: Lujan-Zilbermann J, Warshaw MG, Williams PL, Spector SA, Decker MD, Abzug MJ, Heckman B, Manzella A, Kabat B, Jean-Philippe P, Nachman S, Siberry GK; International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1065 Protocol Team. Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus. J Pediatr. 2012 Oct;161(4):676-81.e2. doi: 10.1016/j.jpeds.2012.04.005. Epub 2012 May 22.
citation: Siberry GK, Warshaw MG, Williams PL, Spector SA, Decker MD, Jean-Philippe P, Yogev R, Heckman BE, Manzella A, Roa J, Nachman S, Lujan-Zilbermann J; IMPAACT P1065 Protocol Team. Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2012 Jan;31(1):47-52. doi: 10.1097/INF.0b013e318236c67b.