Differences in Response to the Flu Vaccine Among Adults With HIV and Without HIV in Uganda

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

To use a systems biological approach to study the molecular signatures of innate and adaptive responses to vaccination in a HIV infected versus uninfected adult population in Kampala, Uganda.

Condition or disease	Intervention/treatment	Phase
HIV; Acquired Immunodeficiency Syndrome; Influenza	Drug: Seasonal trivalent inactivated influenza vaccine (Vaxigrip®)	Not Applicable

Detailed Description:

This longitudinal, observational cohort study will be conducted at the Makerere University- Johns Hopkins University Research Collaboration, at the Mulago National Referral Hospital complex in Kampala Uganda. The study will consist of 2 groups. One group will consist of 25 healthy HIV uninfected adults and the other arm will consist of 35 HIV infected adults. Within the HIV infected arm there will be two groups, 25 HIV infected adults and 10 long term non-progressors. Vaccinees will receive a primary immunization at day 0, and blood samples will be obtained at days 0, 1, 3, 7, 14, 28 and 100 after immunization.

We will analyze the early molecular signatures (identified by microarray analyses, as well as by FACS analyses of innate immune cells and luminex analyses of cytokines and chemokines) that correlate and predict the later immune responses.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	63 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Basic Science
Official Title:	Systems Biological Responses to Influenza Vaccination in an HIV-infected and HIV-uninfected Adult Population in Kampala, Uganda
Study Start Date :	June 2013
Actual Primary Completion Date :	December 2013
Actual Study Completion Date :	March 2014

Arms and Interventions

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Arm	Intervention/treatment
HIV uninfected adults; 25 HIV uninfected adults enrolled at the Mulago National Referral Hospital complex in Kampala, Uganda will receive seasonal trivalent inactivated influenza vaccine (Vaxigrip®).	Drug: Seasonal trivalent inactivated influenza vaccine (Vaxigrip®); Administer seasonal trivalent inactivated influenza vaccine (Vaxigrip®) and collect blood specimens at 0, 1, 3, 7, 14, 28 and 100 days following vaccination.
HIV infected adults on HAART; 25 HIV infected adults enrolled at the Mulago National Referral Hospital complex in Kampala, Uganda will receive seasonal trivalent inactivated influenza vaccine (Vaxigrip®).	Drug: Seasonal trivalent inactivated influenza vaccine (Vaxigrip®); Administer seasonal trivalent inactivated influenza vaccine (Vaxigrip®) and collect blood specimens at 0, 1, 3, 7, 14, 28 and 100 days following vaccination.
HIV-infected long-term non-progressors; 10 HIV-infected long-term non-progressor adults enrolled at the Mulago National Referral Hospital complex in Kampala, Uganda will receive seasonal trivalent inactivated influenza vaccine (Vaxigrip®).	Drug: Seasonal trivalent inactivated influenza vaccine (Vaxigrip®); Administer seasonal trivalent inactivated influenza vaccine (Vaxigrip®) and collect blood specimens at 0, 1, 3, 7, 14, 28 and 100 days following vaccination.

Outcome Measures

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Primary Outcome Measures :

1. In group and between group comparison of immune parameters and gene expressions that change significantly following vaccination with the seasonal trivalent influenza vaccine (Vaxigrip®) [ Time Frame: From baseline (Day 0) to 100 days post vaccination ]
   Immune parameters or gene expressions that change significantly in groups over baseline post immunization and between the study groups will be analyzed. For immune parameters, we will use a two-sided paired t-test. Fold-change will be combined with the test p-value in a selection criterion as appropriate. The tentative selection criterion is p-value ≤ 0.01 and fold change ≥ 3. For the gene/miRNA expression data, we will use the method Significance Analysis of Microarrays (SAM) with paired design to find differentially expressed genes. False discovery rate (FDR) will be used as selection criterion. The tentative selection criterion is FDR ≤ 0.1.
2. Proportion of subjects achieving 4-fold or greater hemagglutination inhibition (HAI)antibody titer increases. [ Time Frame: From baseline (Day 0) to 100 days following primary vaccination ]
   Proportion of subjects in different study groups achieving 4-fold or greater hemagglutination inhibition (HAI)antibody titer increases will be tabulated at each time point (Days 0, 1, 3, 7, 14, 28 and 100) and plotted across time. Fisher's exact test will be used to make comparisons between the study groups.
3. Calculating correlation coefficient between the immune parameter and vaccine immunogenicity, as measured by the humoral immune response against seasonal influenza. [ Time Frame: From baseline (Day 0) to 100 days post vaccination ]
   For immune parameters, we will calculate the correlation coefficient between the immune parameter and vaccine immunogenicity, as measured by the humoral immune response against seasonal influenza. The p-values associated with the correlation coefficients will be used to select immune parameters that are associated with the respective adaptive immune responses. The tentative selection criterion is p-value ≤ 0.01. For gene expression data, we will use the method Significance Analysis of Microarrays (SAM) with quantitative outcome to identify genes that are significantly associated with the immune response. False discovery rate (FDR) will be used as selection criterion. The tentative selection criterion is FDR ≤ 0.1.
4. Characterization of the gut microbiota to determine compositional differences between HIV-uninfected adults versus HIV-infected adults on HAART versus HIV-infected long-term non-progressors [ Time Frame: From baseline (Day 0) to Day 28 post vaccination ]
   Gut mircobiota will be characterized to determine what compositional differences exist between HIV-uninfected adults versus HIV-infected adults on HAARt versus HIV-infected long-term non-progressors at baseline (Day 0), Day 7 and Day 28 post vaccination
5. Correlation between microbiata status and the quality of immune response elicited in vaccinated individuals [ Time Frame: From baseline (Day 0) to Day 28 post vaccination ]
   Determine whether the status of the microbita correlates with the quality of immune responses elicited in vaccinated individuals

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

1. For HIV uninfected group

   • Confirmation of HIV-1 infection from medical records

2. For HIV infected on HAART group

   • Confirmation of HIV-1 infection from medical records
   • Participants must be on HAART for at least 6 months prior to enrollment
   • A CD4 T-cell count available in the last 6 months
   • CD4 T-cell count >350 cells/μL on the eligibility blood specimen

3. Long-term non-progressor group

   • HIV infected for more than 7 years
   • No evidence of opportunistic infections in the medical records
   • Never received antiretroviral therapy (except anti-retrovirals for prevention of mother-to-infant transmission of HIV)
   • A CD4 T-cell count available in the last 6 months
   • CD4+ T-cell count slop of ≥0 cells/µl blood from entry into the MU-JHU cohort until the most recent available CD4+ T-cell count.

Exclusion Criteria:

1. Current moderate or severe acute illness, history of fever or temperature ≥37.5oC within 48 hours prior to vaccination (participants can be re-evaluated at a subsequent visit)
2. History of systemic disease, including: Guillain-Barré Syndrome; known hepatitis B, or hepatitis C infection; cardiac disease; uncontrolled diabetes mellitus (including gestational diabetes); chronic liver condition; clinically significant renal impairment; clinically significant neurological disorders; active TB within the last year; Cancer. This information will be based on self-reporting and (where possible) will be confirmed by hospital medical records
3. Received immunoglobulin or other blood product within the preceding 3 months or expected receipt of blood products during the 3 months of follow-up
4. History of anaphylactic hypersensitivity reactions to egg proteins (eggs or egg products), or any other component of the vaccine including traces (formaldehyde, octoxinol 9 (Triton X-100) and neomycin)
5. History of severe reaction (including hypersensitivity) after receiving any vaccine
6. Currently pregnant
7. In the opinion of the study team it would be unsuitable for the study subjects to receive the vaccine or participate in the study.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

Uganda
Makere University- Johns Hopkins University Research Collaboration, at the Mulago National Referral Hospital
Kampala, Uganda

Sponsors and Collaborators

Emory University

Makerere University

Investigators

Principal Investigator:	Saad B Omer, MBBS,MPH,PhD	Emory Unversity

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D, Pirani A, Gernert K, Deng J, Marzolf B, Kennedy K, Wu H, Bennouna S, Oluoch H, Miller J, Vencio RZ, Mulligan M, Aderem A, Ahmed R, Pulendran B. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol. 2009 Jan;10(1):116-125. doi: 10.1038/ni.1688. Epub 2008 Nov 23.

Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, Pulendran B. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol. 2011 Jul 10;12(8):786-95. doi: 10.1038/ni.2067.

Beck JM, Rosen MJ, Peavy HH. Pulmonary complications of HIV infection. Report of the Fourth NHLBI Workshop. Am J Respir Crit Care Med. 2001 Dec 1;164(11):2120-6.

Malaspina A, Moir S, Orsega SM, Vasquez J, Miller NJ, Donoghue ET, Kottilil S, Gezmu M, Follmann D, Vodeiko GM, Levandowski RA, Mican JM, Fauci AS. Compromised B cell responses to influenza vaccination in HIV-infected individuals. J Infect Dis. 2005 May 1;191(9):1442-50. Epub 2005 Mar 24.

Zanetti AR, Amendola A, Besana S, Boschini A, Tanzi E. Safety and immunogenicity of influenza vaccination in individuals infected with HIV. Vaccine. 2002 Dec 20;20 Suppl 5:B29-32. Review.

Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, Dawson G, Hu W, Leggio C, Washington D, Basser RL. Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med. 2009 Dec 17;361(25):2405-13. doi: 10.1056/NEJMoa0907413. Epub 2009 Sep 10.

Tebas P, Frank I, Lewis M, Quinn J, Zifchak L, Thomas A, Kenney T, Kappes R, Wagner W, Maffei K, Sullivan K; Center for AIDS Research and Clinical Trials Unit of the University of Pennsylvania. Poor immunogenicity of the H1N1 2009 vaccine in well controlled HIV-infected individuals. AIDS. 2010 Sep 10;24(14):2187-92. doi: 10.1097/QAD.0b013e32833c6d5c.

Pallikkuth S, Kanthikeel SP, Silva SY, Fischl M, Pahwa R, Pahwa S. Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients. J Allergy Clin Immunol. 2011 Dec;128(6):1279-85. doi: 10.1016/j.jaci.2011.05.033. Epub 2011 Jul 12.

Wrammert J, Smith K, Miller J, Langley WA, Kokko K, Larsen C, Zheng NY, Mays I, Garman L, Helms C, James J, Air GM, Capra JD, Ahmed R, Wilson PC. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 2008 May 29;453(7195):667-71. doi: 10.1038/nature06890. Epub 2008 Apr 30.

Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O'Donnell CD, Yewdell JW, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med. 2011 Jan 17;208(1):181-93. doi: 10.1084/jem.20101352. Epub 2011 Jan 10. Erratum in: J Exp Med. 2011 Feb 14;208(2):411.

Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011 Jan 28;34(1):108-21. doi: 10.1016/j.immuni.2010.12.012. Epub 2011 Jan 6. Erratum in: Immunity. 2011 Jan 28;34(1):135.

DAIDS table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004, Clarification August 2009. Available at rcc.tech-res-intl.com.

Responsible Party:	Saad B. Omer, PhD, Associate Professor, Emory University
ClinicalTrials.gov Identifier:	NCT01916759 History of Changes
Other Study ID Numbers:	IRB00058919; 1U19AI090023-02 ( U.S. NIH Grant/Contract )
First Posted:	August 6, 2013
Last Update Posted:	April 23, 2014
Last Verified:	April 2014

Keywords provided by Saad B. Omer, PhD, Emory University:

immunization

Additional relevant MeSH terms:

Influenza, Human; Immunologic Deficiency Syndromes; Acquired Immunodeficiency Syndrome; HIV Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases	Immune System Diseases; Lentivirus Infections; Retroviridae Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Slow Virus Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs