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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00459316
• Other study ID #: P1065
• Secondary ID: 10396IMPAACT P10
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 2007
• Est. completion date: March 2013

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 384
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 24 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections
• Meningitis

Intervention

Biological:
• Quadrivalent meningococcal conjugate vaccine
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.

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	Univ. of Maryland Baltimore NICHD CRS	Baltimore	Maryland
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	Miller Children's Hosp. Long Beach CA NICHD CRS	Long Beach	California
United States	Children's Hospital of Los Angeles NICHD CRS	Los Angeles	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	Tulane Univ. New Orleans NICHD CRS	New Orleans	Louisiana
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	University of California, UC San Diego CRS	San Diego	California
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)	International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (10)

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

Centers for Disease Control and Prevention (CDC). Update: Guillain-Barré 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. — View 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. — View 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. Immunogenicit — View 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. Epub 2006 Mar 7. Review. — View 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. — View Citation

Platonov AE, Vershinina IV, Kuijper EJ, Borrow R, Käyhty 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. — View 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 — View 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 (g — View 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 FC? receptor II are associated with antibody res — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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)
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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