Safety of and Immune Response to an H1N1 Influenza Virus Vaccine in HIV Infected Children and Youth

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00992836
First received: October 8, 2009
Last updated: June 23, 2014
Last verified: June 2014
Results First Received: August 23, 2011  
Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Prevention
Conditions: HIV Infections
H1N1 Influenza Virus
Intervention: Biological: Influenza A (H1N1) 2009 monovalent vaccine

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were enrolled from 37 sites between October 14, 2009 and November 12, 2009. Participants were stratified by age in three groups: >=4 to < 9 years old, >=9 to < 18 years old and >=18 to <25 years old.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
One study participant was inadvertently enrolled with acute illness, was not given any vaccination and was immediately taken off study. A second study participant received the first vaccination but it was discovered that he/she was not compliant with the ARV regimen and was taken off study before receiving the second dose of vaccine.

Reporting Groups
  Description
All Study Participants Participants received two doses of the H1N1 influenza virus vaccine, administered 21 days apart. Each dose consisted of two 15-microgram intramuscular injections.

Participant Flow:   Overall Study
    All Study Participants  
STARTED     155  
Received Both Study Vaccinations     150  
COMPLETED     150  
NOT COMPLETED     5  
Lost to Follow-up                 1  
Withdrawal by Subject                 2  
Protocol Violation                 2  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
All Study Participants Participants received two doses of the H1N1 influenza virus vaccine, administered 21 days apart. Each dose consisted of two 15-microgram intramuscular injections.

Baseline Measures
    All Study Participants  
Number of Participants  
[units: participants]
  155  
Age  
[units: years]
Mean ± Standard Deviation
  13  ± 6  
Gender  
[units: participants]
 
Female     76  
Male     79  
Region of Enrollment  
[units: participants]
 
United States     147  
Puerto Rico     8  
Age Strata [1]
[units: Participants]
 
>=4 to < 9 years old     54  
>=9 to < 18 years old     51  
>=18 to < 25 years old     50  
CD4 Cells Count [2]
[units: cells / mm^3]
Mean ± Standard Deviation
  568  ± 242  
Percentage of CD4 Cells [3]
[units: percentage]
Mean ± Standard Deviation
  29  ± 11  
[1] Study participants were stratified by age into three groups.
[2] This measures the number of CD4 cells.
[3] This measures the percentage of CD4 cells.



  Outcome Measures
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1.  Primary:   The Number of Participants Who Had at Least One Adverse Event (AE)   [ Time Frame: Measured up to 7 months after vaccination ]

Measure Type Primary
Measure Title The Number of Participants Who Had at Least One Adverse Event (AE)
Measure Description

Shows the number of participants who had at least one adverse event (AE) in each category. The AEs include: abnormal laboratory values, signs and symptoms, or diagnoses; solicited local AEs; and solicited systemic AEs.

Adverse Events were graded using the DAIDS Grading Severity of AEs (see Link under More Information), as follows: grade 1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death.

Time Frame Measured up to 7 months after vaccination  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
All Study Participants All 155 study participants are included in this analysis.

Measured Values
    All Study Participants  
Number of Participants Analyzed  
[units: participants]
  155  
The Number of Participants Who Had at Least One Adverse Event (AE)  
[units: participants]
 
Overall (New AEs after start of treatment)     113  
Grade 4 AEs (New, after start of treatment)     0  
Grade 3 AEs (New, after start of treatment)     7  
Grade 2 local and systemic AEs to injection     6  

No statistical analysis provided for The Number of Participants Who Had at Least One Adverse Event (AE)



2.  Primary:   The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine   [ Time Frame: Measured up to 7 months after vaccination ]

Measure Type Primary
Measure Title The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine
Measure Description Shows the number of participants who experienced any events that were thought to be at least possibly related to study treatment. Adverse Events were graded using the DAIDS Grading Severity of AEs (see Link under More Information), as follows: grade 1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death.
Time Frame Measured up to 7 months after vaccination  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The 154 study participants who received at last one vaccination are included in this analysis.

Reporting Groups
  Description
Vaccinated Study Participants The 154 study participants who received at last one vaccination are included in this analysis.

Measured Values
    Vaccinated Study Participants  
Number of Participants Analyzed  
[units: participants]
  154  
The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine  
[units: participants]
  7  

No statistical analysis provided for The Number of Participants Who Had at Least One AE Attributed to the Study Vaccine



3.  Primary:   Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose   [ Time Frame: Measured at Day 21 ]

Measure Type Primary
Measure Title Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose
Measure Description No text entered.
Time Frame Measured at Day 21  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The 154 study participants who received at last one vaccination are included in this analysis.

Reporting Groups
  Description
Vaccinated Study Participants The 154 study participants who received at last one vaccination are included in this analysis.

Measured Values
    Vaccinated Study Participants  
Number of Participants Analyzed  
[units: participants]
  154  
Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose  
[units: participants]
  0  

No statistical analysis provided for Withholding of Second Vaccine Dose Due to Adverse Reactions Attributed to First Dose



4.  Primary:   Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40   [ Time Frame: Measured at 21 days after first dose and 10 days after second dose ]

Measure Type Primary
Measure Title Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40
Measure Description Antibodies to Influenza A (H1N1) 2009 were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640 and >=1280. Seroprotection was defined as having a titer of >=40 following vaccination.
Time Frame Measured at 21 days after first dose and 10 days after second dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The HAI titers following the first vaccination were summarized for the eligible study participants who received at least one vaccine and had nonmissing HAI data, and the titers following the second vaccination for the eligible study participants who received both doses of vaccine and had nonmissing HAI data.

Reporting Groups
  Description
Overall The total N for these analyses were 140 and 142, for the analysis of antibody titers after the first and second vaccinations, respectively.

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  142  
Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40  
[units: percentage of participants]
Number ( 95% Confidence Interval )
 
Post dose 1 (N=140)     72.1  
  ( 63.9 to 79.4 )  
Post dose 2 (N=142)     82.4  
  ( 75.1 to 88.3 )  

No statistical analysis provided for Percent of Participants With a Hemagglutinin Inhibition (HAI) Titer of >=40



5.  Secondary:   Percent of Participants With an HAI Titer >=40 at Long-term Follow-up   [ Time Frame: Measured at 6 months after second dose ]

Measure Type Secondary
Measure Title Percent of Participants With an HAI Titer >=40 at Long-term Follow-up
Measure Description No text entered.
Time Frame Measured at 6 months after second dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The HAI titers were summarized for the eligible study participants who received both doses of vaccine and had nonmissing HAI data.

Reporting Groups
  Description
Overall The total N for this analysis was 138, those who received both vaccinations and had nonmissing data.

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  138  
Percent of Participants With an HAI Titer >=40 at Long-term Follow-up  
[units: percentage of participants]
Number ( 95% Confidence Interval )
  57.2  
  ( 48.5 to 65.6 )  

No statistical analysis provided for Percent of Participants With an HAI Titer >=40 at Long-term Follow-up



6.  Secondary:   Geometric Mean Antibody Titers (GMT) HAI   [ Time Frame: Measured after first and second doses and 6 months after second dose ]

Measure Type Secondary
Measure Title Geometric Mean Antibody Titers (GMT) HAI
Measure Description Presents the value of the geometric mean titer at each time point.
Time Frame Measured after first and second doses and 6 months after second dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The HAI titers following the first vaccination were summarized for the eligible study participants who received at least one vaccine and had nonmissing HAI data, and the titers following the second vaccination for the eligible study participants who received both doses of vaccine and had nonmissing HAI data.

Reporting Groups
  Description
Overall The total N for these analyses were 140, 142 and 138, for the analysis of antibody titers after the first and second vaccinations and after 6 months after the second vaccination, respectively.

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  142  
Geometric Mean Antibody Titers (GMT) HAI  
[units: titers]
Geometric Mean ( 95% Confidence Interval )
 
At 21 days after the first vaccination (N=140)     85  
  ( 65 to 111 )  
At 10 days after the second vaccination (N=142)     127  
  ( 101 to 159 )  
At 6 months after the second vaccination (N=138)     33  
  ( 27 to 40 )  

No statistical analysis provided for Geometric Mean Antibody Titers (GMT) HAI



7.  Secondary:   Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values   [ Time Frame: Measured at entry, 21 days after first dose, and 10 days after second dose ]

Measure Type Secondary
Measure Title Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values
Measure Description The median and interquartile range (IQR) of B-Cell ELISPOT-measured IgG antibody-secreting cells (ASC)/10^6 peripheral blood mononucleated cell (PBMC) and the median and interquartile range (IQR) of T-Cell ELISPOT-measured pH1N1 IFNgamma spot-forming cells (SFC)/10^6 PBMC.
Time Frame Measured at entry, 21 days after first dose, and 10 days after second dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The participants who had received all doses of vaccine up to that timepoint and had sufficient samples for testing.

Reporting Groups
  Description
Overall The total N for this analysis was 68, those who received the vaccinations and had enough samples for testing.

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  68  
Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values  
[units: ASC or SFC/10^6 PBMC]
Median ( Inter-Quartile Range )
 
IgG ASC/10^6 PBMC, Week 0 (N=46)     6  
  ( 2 to 16 )  
IgG ASC/10^6 PBMC, Post Dose 1 (N=40)     13  
  ( 4 to 40 )  
IgG ASC/10^6 PBMC, Post Dose 2 (N=40)     12  
  ( 5 to 25 )  
pH1N1 IFNgamma SFC/10^6 PBMC, Week 0 (N=68)     317  
  ( 117 to 673 )  
pH1N1 IFNgamma SFC/10^6 PBMC, Post Dose 1 (N=68)     363  
  ( 123 to 622 )  
pH1N1 IFNgamma SFC/10^6 PBMC, Post Dose 2 (N=65)     261  
  ( 78 to 525 )  

No statistical analysis provided for Cell-mediated Immune Responses, Measured by B-cell and T-cell Enzyme-linked Immunosorbent Spot (ELISPOT) Assay Values



8.  Secondary:   HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV)   [ Time Frame: Measured at entry, 21 days after first dose, and 10 days and 6 months after second dose ]

Measure Type Secondary
Measure Title HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV)
Measure Description Presents the value of the median titer as well as the interquartile range at study entry. Antibodies to seasonal Influenza vaccine were measured using an HAI assay. The potential titer read-outs from the assay used were <10 (considered undetectable), 10, 20, 40, 60, 80, 160, 320, 640, and >=1280.
Time Frame Measured at entry, 21 days after first dose, and 10 days and 6 months after second dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The participants who had received all doses of vaccine up to that timepoint and had sufficient samples for testing.

Reporting Groups
  Description
Influenza A (H1N1) 2009 Monovalent Vaccine

All participants received two doses of the H1N1 influenza virus vaccine, administered 21 days apart.

Influenza A (H1N1) 2009 monovalent vaccine: Two doses of vaccine, delivered 21 days apart, with each dose consisting of two 15-microgram intramuscular injections


Measured Values
    Influenza A (H1N1) 2009 Monovalent Vaccine  
Number of Participants Analyzed  
[units: participants]
  123  
HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV)  
[units: titer]
Median ( Inter-Quartile Range )
 
Week 0 (N=123)     40  
  ( 20 to 80 )  
Post Dose 1 (N=121)     40  
  ( 20 to 80 )  
Post Dose 2 (N=121)     40  
  ( 20 to 80 )  
6 months Post Dose 2 (N=122)     40  
  ( 20 to 80 )  

No statistical analysis provided for HAI Titers Against Seasonal Influenza Viruses Containing Trivalent Influenza Vaccine (TIV)



9.  Secondary:   Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens   [ Time Frame: Measured at entry, 21 days after first dose, and 10 days after second dose ]

Measure Type Secondary
Measure Title Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens
Measure Description

The TIV assay was not performed due to lack of available cells after completion of other planned assays.

The median and interquartile range (IQR) of T-Cell ELISPOT-measured pH1N1 Granzyme B spot-forming cells (SFC)/10^6 peripheral blood mononucleated cell (PBMC).

The median and interquartile range (IQR) of T-Cell ELISPOT-measured PHA INFgamma spot-forming cells (SFC)/10^6 PBMC.

The median and interquartile range (IQR) of T-Cell ELISPOT-measured PHA Granzyme B spot-forming cells (SFC)/10^6 PBMC.

Time Frame Measured at entry, 21 days after first dose, and 10 days after second dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The participants who had received all doses of vaccine up to that timepoint and had sufficient samples for testing.

Reporting Groups
  Description
Overall The total N for this analysis was 68, those who received the vaccinations and had enough samples for testing.

Measured Values
    Overall  
Number of Participants Analyzed  
[units: participants]
  68  
Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens  
[units: SFC/10^6 PBMC]
Median ( Inter-Quartile Range )
 
pH1N1 Granzyme B SFC/10^6 PBMC, Week 0 (N=64)     35  
  ( 0 to 220 )  
pH1N1 Granzyme B SFC/10^6 PBMC, Week 3 (N=62)     26  
  ( 0 to 170 )  
pH1N1 Granzyme B SFC/10^6 PBMC, Week 5 (N=61)     30  
  ( 0 to 220 )  
PHA INFgamma SFC/10^6 PBMC, Week 0 (N=68)     699  
  ( 307 to 1010 )  
PHA INFgamma SFC/10^6 PBMC, Week 3 (N=68)     637  
  ( 261 to 965 )  
PHA INFgamma SFC/10^6 PBMC, Week 5 (N=65)     624  
  ( 263 to 1000 )  
PHA Granzyme B SFC/10^6 PBMC, Week 0 (N=64)     3250  
  ( 390 to 7465 )  
PHA Granzyme B SFC/10^6 PBMC, Week 3 (N=62)     3340  
  ( 510 to 7520 )  
PHA Granzyme B SFC/10^6 PBMC, Week 5 (N=60)     2045  
  ( 300 to 7825 )  

No statistical analysis provided for Cell-mediated Immune Responses to Influenza Viruses Contained in TIV and Other Antigens




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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