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

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.

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