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

Study Overview
=================
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.

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

Conditions
-----------------
HIV Infections, Meningitis

Intervention / Treatment
-----------------
* Biological: Quadrivalent meningococcal conjugate vaccine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 24 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Participants ≤11 to <25 years of age with CD4% at screening ≥15%. All received Quadrivalent meningococcal conjugate vaccine at entry, those who were eligible were randomized at week 24, with Group 1B receiving a second Quadrivalent meningococcal conjugate vaccine at week 24. Those who were eligible received a booster dose of Quadrivalent meningococcal vaccine at 3.5 years. | Biological: Quadrivalent meningococcal conjugate vaccine<br>* MCV4 vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier ) was given by injection intramuscularly at least once and no more than three times for each participant, depending on adverse reactions.<br>* Other names: MCV4;|
| Experimental: Group 2<br>Participants ≤11 to <25 years of age with CD4% at screening <15%; All receiving Quadrivalent meningococcal conjugate vaccine at entry, with those who were eligible receiving Quadrivalent meningococcal conjugate vaccine at week 24 and 3 years. | Biological: Quadrivalent meningococcal conjugate vaccine<br>* MCV4 vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier ) was given by injection intramuscularly at least once and no more than three times for each participant, depending on adverse reactions.<br>* Other names: MCV4;|
| Experimental: Group 3<br>Participants >=2 to <11 years of age with CD4% at screening ≥ 25%; All received Quadrivalent meningococcal conjugate vaccine at entry, with those who were eligible receiving Quadrivalent meningococcal conjugate vaccine at week 24 and 3 years. | Biological: Quadrivalent meningococcal conjugate vaccine<br>* MCV4 vaccine (4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier ) was given by injection intramuscularly at least once and no more than three times for each participant, depending on adverse reactions.<br>* Other names: MCV4;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Serum bactericidal antibody titers were measured at study entry and Week 28 for each of the four serogroups in the MCV-4 vaccine. Response was defined as a 4-fold or greater increase from entry at Week 28. | Study entry and Week 28 | 
| 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) | Serum bactericidal antibody titers were measured at study entry and Week 4 for each of the four serogroups in the MCV-4 vaccine. Response (seroconversion) was defined as a 4-fold or greater increase from entry at Week 4. | At Study entry, Week 4 | 
| Long-term Immunogenicity, as Assessed by Number of Participants With Protective Levels of Antibody at Week 72 | Protective levels of antibody are titers ≥1:128. | Week 72 | 
| Number of Participants With Grade 3 or Higher Adverse Events Within 42 Days Following Dose 1 of the Vaccine. | Adverse events were graded by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December, 2004, Clarification August 2009, which is available on the RSC web site (http://rsc.tech-res.com/safetyandpharmacovigilance/). Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = potentially life-threatening, Grade 5 = death. | From administration of Dose 1 at week 0 to 42 days post-vaccination | 
| Number of Participants With Reactions and Grade 3 or Higher Adverse Events Within 42 Days Following Dose 2 of the Vaccine. | Adverse events were graded by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December, 2004, Clarification August 2009, which is available on the RSC web site (http://rsc.tech-res.com/safetyandpharmacovigilance/). Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = potentially life-threatening, Grade 5 = death. | From administration of Dose 2 at week 24 to 6 weeks post-vaccination | 
| Number of Participants With Immunogenicity at Step 3 Entry | Immunogenicity was assessed for each serogroup by the number of participants with protective antibody levels (titers greater than or equal to 1:128) | At 3.5 years (Step 3 entry) | 
| Number of Participants With 4-fold Memory Response in Step 3 | Defined for each serogroup as a four-fold rise in antibody titers between booster dose (week 0) and week 1. | Step 3 entry and Week 1 post-booster vaccine | 
| Number of Participants With Seropositive Memory Response (in Step 3) | Seropositive memory response was defined for each serogroup by having protective antibody levels (titer >= 1:128) on Day 0 or change from seronegative to seropositive between booster dose (Day 0) and Day 7. | Step 3 entry and Week 1 post-booster vaccine | 
| Number of Participants With Primary Response (in Step 3) | Primary response was defined for each serogroup as 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. Note: a primary response can only occur in the absence of any memory response. | Step 3 entry and Week 4 post-booster vaccine | 
| Number of Participants With Immunogenicity at Step 3 Weeks 4 and 24 | Immunogenicity was assessed by the number of participants with protective levels of antibody (titers greater than or equal to 1:128) | At Step 3 Weeks 4 and 24 post-booster vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenic Response to Serogroup C in Group 2 | Immunogenic response as assessed by number of participants with protective antibody titers (>= 1:128) to serogroup C in Group 2 (entry CD4%<15) | At Weeks 4, 28, and 72 | 
| Number of Participants With Protective Antibody Titers for Serogroup C at Step 3 Entry | Number of participants with protective antibody titers (rSBA>=1:128) for serogroup C by treatment arm (1 vs. 2 doses) of Group 1 (entry CD4% >= 15) at Step 3 entry | At 3.5 years | 
| Immunologic Memory for Serogroup C by Treatment Arm (1 vs. 2 Doses) | Evidence of immunologic memory according to each of the following definitions: Secondary (anamnestic) response defined as a four-fold rise in Ab titers between day 0 (booster dose) and day 7; or Seroprotection on day 0 or change from titer <1:128 to titer ≥1:128 (seroprotection) between day 0 and day 7. | At Week 1 post-booster vaccination | 
| Immunologic Memory or Primary Response for Serogroup C by Treatment Arm | Immunologic Memory defined as: Secondary (anamnestic) response defined as a four-fold rise in Ab titers between day 0 (booster dose) and day 7; or Seroprotection on day 0 or change from titer <1:128 to titer ≥1:128 (seroprotection) between day 0 and day 7. Primary Response defined as: 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 titer <1:128 on day 0 to titer ≥1:128on day 28, but not between day 0 and day 7. | At Week 4 post-booster vaccination | 
| 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. | Adverse events were graded by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December, 2004, Clarification August 2009, which is available on the RSC web site (http://rsc.tech-res.com/safetyandpharmacovigilance/). Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = potentially life-threatening, Grade 5 = death. | From administration of vaccination at Step 3 entry through 6 weeks post-vaccination |