Safety of and Immune Response to a Meningitis Vaccine in HIV-Infected Children and Youth - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Information provided by (Responsible Party):	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00459316

Purpose

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 is to determine the safety of and immune response to a preventive meningitis vaccine in HIV-infected youth.

Condition	Intervention	Phase
HIV Infections Meningitis	Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) booster	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
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

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency

MedlinePlus related topics: HIV/AIDS Memory Meningitis

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Comparison of immunogenic response rates , as assessed by proportion of seroconverters for meningitis serogroup C, between treatment arms (1 vs. 2 doses) of Group 1 [ Time Frame: At Week 28 ] [ Designated as safety issue: No ]
Short-term immunogenicity, as assessed by proportion of seroconverters for serogroup C [ Time Frame: At Weeks 4 and 24 ] [ Designated as safety issue: No ]
Long-term immunogenicity, as assessed by proportion of seroconverters [ Time Frame: At Week 72 ] [ Designated as safety issue: No ]
Safety, as assessed by number and percentage of participants with reactions and Grade 3 or higher adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Immunogenic response rates after 2 doses (Group 3) [ Time Frame: At Week 28 ] [ Designated as safety issue: No ]
Immunogenicity, as assessed by GMTs, median titers, and the proportion of participants with protective antibody levels (titers greater than or equal to 1:128) in Step 3 [ Time Frame: At 3.5 years ] [ Designated as safety issue: No ]
Memory response (in Step 3), as defined by a four-fold rise in Ab titers between booster dose (Day 0) and Day 7 [ Time Frame: At Week 1 ] [ Designated as safety issue: No ]
Memory response (in Step 3), as defined by seropositivity on Day 0 or change from seronegative to seropositive between booster dose (Day 0) and Day 7 [ Time Frame: At Week 1 ] [ Designated as safety issue: No ]
Primary response (in Step 3), as defined a four-fold rise in Ab concentration between day 0 and day 28, but not between day 0 and day 7; OR a change from seronegative on day 0 to seropositive on day 28, but not between day 0 and day 7 [ Time Frame: At Week 4 ] [ Designated as safety issue: No ]
Immunogenicity, as assessed by proportion of participants with protective levels of antibody (titers greater than or equal to 1:128) [ Time Frame: At Weeks 4 and 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Short-term immunogenicity, as assessed by proportion of seroconverters to serogroup C in each stratum of Group 1 [ Time Frame: At Weeks 4 and 24 ] [ Designated as safety issue: No ]
Long-term immunogenicity, as assessed by proportion of seroconverters to serogroup C [ Time Frame: At Weeks 28 and 72 ] [ Designated as safety issue: No ]
Proportion of seroconverters in Group 1A (1 dose), as compared to the proportion of seroconverters in Group 1B (2 doses) [ Time Frame: At Week 72 ] [ Designated as safety issue: No ]
Occurrence of Grade 3 or higher adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Immunogenic response as assessed by proportion of seroconverters to serogroup C in Group 2 [ Time Frame: At Weeks 4, 28, and 72 ] [ Designated as safety issue: No ]
Comparison of responders and non-responders by genetic determinants [ Time Frame: At Weeks 4, 24, 28, and 72 ] [ Designated as safety issue: No ]
Comparison of the proportion of participants with protective antibody titers for serogroup C between treatment arms (1 vs. 2 doses) of Group 1 (Step 3) [ Time Frame: At 3.5 years ] [ Designated as safety issue: No ]
Comparison of memory response for serogroup C between treatment arms (1 vs. 2 doses) of Group 1 (Step 3) [ Time Frame: At Week 1 post-booster vaccination ] [ Designated as safety issue: No ]
Comparison of response (memory or primary) for serogroup C between treatment arms (1 vs. 2 doses) of Group 1 (Step 3) [ Time Frame: At Week 4 post-booster vaccination ] [ Designated as safety issue: No ]
Comparison of immunogenicity, as assessed by proportion of participants with protective levels of antibody (titers great than or equal to 1:128), between treatment arms (1 vs. 2 doses) of Group 1 (Step 3) [ Time Frame: At Weeks 4 and 24 post-booster vaccination ] [ Designated as safety issue: No ]
Safety of booster vaccine, as assessed by number and percent of subjects with documented reactions to the vaccine and with new grade 3 or higher adverse events [ Time Frame: Throughout study (Step 3) ] [ Designated as safety issue: Yes ]

Enrollment:	384
Study Start Date:	June 2007
Estimated Primary Completion Date:	February 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 Participants aged 11 to 24 with a CD4 percentage of or greater than 15%	Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) MCV4 vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier ) will be given by injection intramuscularly at least once and no more than two times for each participant, depending on adverse reactions. Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) booster MCV4 booster vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier) will be given by injection intramuscularly at 3.5 years post initial vaccination
Experimental: 2 Participants aged 11 to 24 with a CD4 percentage of or less than 15%	Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) MCV4 vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier ) will be given by injection intramuscularly at least once and no more than two times for each participant, depending on adverse reactions.
Experimental: 3 Participants aged 2 to 10 with a CD4 percentage of or greater than 25%	Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) MCV4 vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier ) will be given by injection intramuscularly at least once and no more than two times for each participant, depending on adverse reactions. Biological: Quadrivalent meningococcal conjugate vaccine (MCV4) booster MCV4 booster vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier) will be given by injection intramuscularly at 3.5 years post initial vaccination

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 is to determine the safety and immunogenicity of MCV4 in HIV-infected youth 2 to 24 years of age.

This study will last 72 weeks. Participants in this study will be stratified according to CD4 percentage (CD4%) and age. Participants aged 11 to 24 with a CD4% of 15% or higher will be a part of Group 1. Group 1 will include two cohorts. Cohort 1 will consist of youth with a CD4% between 15% and 24%. Cohort 2 will consist of youth with a CD4% of 25% or higher. Participants aged 11 to 24 with a CD4% of lower than 15% will join Group 2. Participants aged 2 to 10 with a CD4% of 25% or higher will join Group 3.

At study entry, all study participants will receive one injection of MCV4. Participants will be observed for 30 minutes post-injection to monitor for adverse events. A clinic visit is required 24 hours post-injection if the participant reports adverse events. Participants in Group 1 who did not experience any adverse events after the first injection will be randomly assigned to Group 1A or Group 1B at Week 24. Group 1B, Group 2, and Group 3 participants who had no adverse events after the first injection will receive a second injection of MCV4 at Week 24.

There will be five study visits; they will occur 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 will occur. In addition, study participants will be 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 receive a second injection will be 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 will receive a booster dose of MCV4 at approximately 3.5 years (+/- 6 months) after the initial MCV4 vaccination. Participants will then be observed for 30 minutes post-injection to monitor for adverse events. Participants will also be observed at Week 1 for vaccine adverse reactions.

This portion of the study (Step 3) will last an additional 24 weeks. There will be 4 study visits; they will occur 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 will occur. The purpose of this follow-up study is 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

Ages Eligible for Study:	2 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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
Patients and/or their partners who are sexually active must agree to use at least one of the following methods of contraception as long as they are on the study: hormonal birth ctronol 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 previous versions of P1065 and stratified into Group 1 or 3
Participants do NOT have to be less than 25 years of age
Participants must have serology data from Weeks 0, 4, and 28 from their previous participation in P1065
Subject must be 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 currently taking G-CSF or erythropoietin are 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, may interfere 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 will be followed to 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 patient or patient'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 requires treatment with medications that are 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
Subjects for whom long-term corticosteroid therapy (greater than or equal to 2 weeks) is anticipated are excluded [Note: non-steroidal anti-inflammatory agents and inhaled, intranasal and topical corticosteroids are 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 investigator judges to be clinically significant (other than HIV infection) or clinically significant findings since enrollment into P1065 that, in the investigator's opinion, would compromise the outcome of this study
Any new greater than or equal to grade 3 clinical toxicity that is not related to vaccine and has not resolved within 2 weeks before entry into Step 3

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00459316

Show 37 Study Locations

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Investigators

Study Chair:	George K. Siberry, MD, MPH	Pediatric, Adolescent, and Maternal AIDS (PAMA) Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Study Chair:	Jorge Lujan-Zilbermann, MD, MS	Division of Infectious Diseases, Department of Pediatrics, University of South Florida College of Medicine

More Information

Additional Information:

Haga clic aquí para ver información sobre este ensayo clínico en español. This link exits the ClinicalTrials.gov site

Publications:

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.

Campos-Outcalt D. Meningococcal vaccine: New product, new recommendations. J Fam Pract. 2005 Apr;54(4):324-6. Review.

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. Erratum in: MMWR Morb Mortal Wkly Rep. 2006 Nov 3;55(43):1177.

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.

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. Epub 2006 Mar 7. Review.

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.

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.

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00459316 History of Changes
Other Study ID Numbers:	P1065, 10396, IMPAACT P1065, PACTG P1065
Study First Received:	April 10, 2007
Last Updated:	May 17, 2012
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

HIV Infections
Acquired Immunodeficiency Syndrome
Meningitis
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral

Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases

ClinicalTrials.gov processed this record on May 23, 2012