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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02765126




Registration number
NCT02765126
Ethics application status
Date submitted
3/05/2016
Date registered
6/05/2016
Date last updated
27/07/2017

Titles & IDs
Public title
Heterologous Effect of Diptheria, Tetanus, Acellular Pertussis Vaccination on Influenza Challenge in the Elderly
Scientific title
Clifford Craig Vaccine Trial Centre: Heterologous Effect of Diptheria, Tetanus, Acellular Pertussis Vaccination on Influenza Vaccine Challenge in the Elderly
Secondary ID [1] 0 0
H0015460
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heterologous Effects of Vaccines 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Seasonal influenza vaccine
Other interventions - Diphtheria-tetanus-acellular pertussis vaccine

Active Comparator: Group 1 - Diphtheria-tetanus-acellular pertussis vaccine administered day 0, followed by seasonal influenza vaccination four weeks later. Blood testing to occur day 0 (prior to vaccine administration), 24 hours, 1 week, 4 weeks, 4 weeks + 24 hours, 5 weeks, 8 weeks and 30 weeks. Stool samples to be taken at day 0 and 1 week post-vaccination.

Active Comparator: Group 2 - Seasonal influenza vaccine administered on day 0, to be offered DTP vaccine at week 26. Blood testing to occur day 0 (prior to vaccine administration), 24 hours, 1 week 1, 4 weeks and 26 weeks. Stool samples to be taken at day 0 and 1 week post-vaccination.

Active Comparator: Group 3 - Seasonal influenza vaccine and DTP vaccine administered together on day 0. Blood testing to occur day 0 (prior to vaccine administration), 24 hours, 1 week 1, 4 weeks and 26 weeks. Stool samples to be taken at day 0 and 1 week post-vaccination.


Other interventions: Seasonal influenza vaccine
Intramuscular standard seasonal influenza vaccine

Other interventions: Diphtheria-tetanus-acellular pertussis vaccine
Intramuscular DTaP vaccine

Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of inflammation reactive TNFR2+ regulatory T cells per mL of blood - Change over time in different vaccine groups of Tregs measured by flow cytometry.
Timepoint [1] 0 0
24 hours, 1 week, 4 weeks and 26 weeks
Secondary outcome [1] 0 0
Whole human genome transcription profile by next generation sequencing in log2 expression levels - Differential gene expression 24 hours after vaccination compared to baseline, and vaccine groups compared to see which genes / pathways are affected. Differential transcription determined for each gene, then analysed using modular analysis tools to determine vaccine effects.
Timepoint [1] 0 0
24 hours
Secondary outcome [2] 0 0
Influenza-specific antibody titres to seasonal influenza vaccination - Change over time in the different vaccine groups of titres measured by haemagglutination inhibition assay.
Timepoint [2] 0 0
4 weeks and 26 weeks
Secondary outcome [3] 0 0
Pro-inflammatory (TNF) to anti-inflammatory (IL-10) cytokine ratio in stimulated blood in pg/mL - Change in TNF:IL-10 ratio post-vaccination over time as measured by cytokine multiplex assay of anti-CD3 stimulated PBMC.
Timepoint [3] 0 0
24 hours, 1 week, 4 weeks and 26 weeks
Secondary outcome [4] 0 0
Influenza-specific IFN-g CD4 T cell responses to seasonal influenza vaccination in pg/mL - Change over time in the different vaccine groups of IFN-g levels in supernatants from CD4 T cells cultured with live influenza virus
Timepoint [4] 0 0
4 weeks and 26 weeks

Eligibility
Key inclusion criteria
- Two study groups 30-50 years old >65 years old
Minimum age
30 Years
Maximum age
100 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Unwell on day of vaccination

- Temperature >38°C

- Active cancer

- Active autoimmune disease

- Diabetes mellitus

- Taking immunosuppressive drugs including steroids

- Any vaccination in last 3 months

- DT or DTaP vaccination in the last year

- Known allergy or contraindication to influenza or DTaP vaccination

- Pregnant or breastfeeding

Study design
Purpose of the study
Basic Science
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
TAS
Recruitment hospital [1] 0 0
Clifford Craig Foundation - Launceston
Recruitment postcode(s) [1] 0 0
7250 - Launceston

Funding & Sponsors
Primary sponsor type
Other
Name
Clifford Craig Medical Research Trust
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Monash University
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
The Peter Doherty Institute for Infection and Immunity
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
University of Sao Paulo
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Johns Hopkins Bloomberg School of Public Health
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Vaccines can have non-targeted or heterologous (also called non-specific) immunological
effects on the immune system i.e. effects other than inducing an immune response against the
disease targeted by the vaccine. This trial aims to evaluate the non-specific immunological
effects of two vaccines - diphtheria-tetanus-acellular pertussis (DTP) vaccine and seasonal
influenza vaccine - in a cohort of elderly humans (>65 years of age) and healthy adult
control subjects (30-50 years).
Trial website
https://clinicaltrials.gov/show/NCT02765126
Trial related presentations / publications
Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 –- conclusions and recommendations. Wkly Epidemiol Rec. 2014 May 23;89(21):221-36. English, French.
Aaby P, Martins CL, Garly ML, Balé C, Andersen A, Rodrigues A, Ravn H, Lisse IM, Benn CS, Whittle HC. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010 Nov 30;341:c6495. doi: 10.1136/bmj.c6495.
Sørup S, Benn CS, Poulsen A, Krause TG, Aaby P, Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA. 2014 Feb 26;311(8):826-35. doi: 10.1001/jama.2014.470.
Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open. 2012 May 22;2(3). pii: e000707. doi: 10.1136/bmjopen-2011-000707. Print 2012.
Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007 Oct 4;357(14):1373-81.
Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006 Feb 20;24(8):1159-69. Epub 2005 Sep 19. Review.
Sasaki S, Sullivan M, Narvaez CF, Holmes TH, Furman D, Zheng NY, Nishtala M, Wrammert J, Smith K, James JA, Dekker CL, Davis MM, Wilson PC, Greenberg HB, He XS. Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. J Clin Invest. 2011 Aug;121(8):3109-19. doi: 10.1172/JCI57834. Epub 2011 Jul 25.
Grant EJ, Chen L, Quiñones-Parra S, Pang K, Kedzierska K, Chen W. T-cell immunity to influenza A viruses. Crit Rev Immunol. 2014;34(1):15-39. Review.
Saurwein-Teissl M, Lung TL, Marx F, Gschösser C, Asch E, Blasko I, Parson W, Böck G, Schönitzer D, Trannoy E, Grubeck-Loebenstein B. Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol. 2002 Jun 1;168(11):5893-9.
Weston WM, Friedland LR, Wu X, Howe B. Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix(®)): results of two randomized trials. Vaccine. 2012 Feb 21;30(9):1721-8. doi: 10.1016/j.vaccine.2011.12.055. Epub 2011 Dec 31.
Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012 Oct;24(5):331-41. doi: 10.1016/j.smim.2012.04.008. Epub 2012 May 4. Review.
Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol. 2010 Mar 1;184(5):2518-27. doi: 10.4049/jimmunol.0901022. Epub 2010 Jan 25.
Baylis D, Bartlett DB, Syddall HE, Ntani G, Gale CR, Cooper C, Lord JM, Sayer AA. Immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people. Age (Dordr). 2013 Jun;35(3):963-71. doi: 10.1007/s11357-012-9396-8. Epub 2012 Mar 3.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007 Jan;128(1):92-105. Epub 2006 Nov 20. Review.
Bruunsgaard H, Andersen-Ranberg K, Hjelmborg Jv, Pedersen BK, Jeune B. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med. 2003 Sep;115(4):278-83.
Nikolich-Žugich J, Li G, Uhrlaub JL, Renkema KR, Smithey MJ. Age-related changes in CD8 T cell homeostasis and immunity to infection. Semin Immunol. 2012 Oct;24(5):356-64. doi: 10.1016/j.smim.2012.04.009. Epub 2012 May 1. Review.
Ndure J, Flanagan KL. Targeting regulatory T cells to improve vaccine immunogenicity in early life. Front Microbiol. 2014 Sep 11;5:477. doi: 10.3389/fmicb.2014.00477. eCollection 2014. Review.
Crimeen-Irwin B, Scalzo K, Gloster S, Mottram PL, Plebanski M. Failure of immune homeostasis -- the consequences of under and over reactivity. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Dec;5(4):413-22. Review.
Govindaraj C, Scalzo-Inguanti K, Scholzen A, Li S, Plebanski M. TNFR2 Expression on CD25(hi)FOXP3(+) T Cells Induced upon TCR Stimulation of CD4 T Cells Identifies Maximal Cytokine-Producing Effectors. Front Immunol. 2013 Aug 6;4:233. doi: 10.3389/fimmu.2013.00233. eCollection 2013.
Wilson KL, Xiang SD, Plebanski M. Montanide, Poly I:C and nanoparticle based vaccines promote differential suppressor and effector cell expansion: a study of induction of CD8 T cells to a minimal Plasmodium berghei epitope. Front Microbiol. 2015 Feb 6;6:29. doi: 10.3389/fmicb.2015.00029. eCollection 2015.
Chen X, Hamano R, Subleski JJ, Hurwitz AA, Howard OM, Oppenheim JJ. Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3- conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol. 2010 Jul 1;185(1):174-82. doi: 10.4049/jimmunol.0903548. Epub 2010 Jun 4.
Flanagan KL, van Crevel R, Curtis N, Shann F, Levy O; Optimmunize Network. Heterologous ("nonspecific") and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clin Infect Dis. 2013 Jul;57(2):283-9. doi: 10.1093/cid/cit209. Epub 2013 Apr 9. Review.
Nakaya HI, Li S, Pulendran B. Systems vaccinology: learning to compute the behavior of vaccine induced immunity. Wiley Interdiscip Rev Syst Biol Med. 2012 Mar-Apr;4(2):193-205. doi: 10.1002/wsbm.163. Epub 2011 Oct 19. Review.
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.
Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiébaut R, Tibshirani RJ, Davis MM. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):869-74. doi: 10.1073/pnas.1321060111. Epub 2013 Dec 23.
Yao X, Hamilton RG, Weng NP, Xue QL, Bream JH, Li H, Tian J, Yeh SH, Resnick B, Xu X, Walston J, Fried LP, Leng SX. Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. Vaccine. 2011 Jul 12;29(31):5015-21. doi: 10.1016/j.vaccine.2011.04.077. Epub 2011 May 10.
Chen X, Oppenheim JJ. TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Curr Dir Autoimmun. 2010;11:119-34. doi: 10.1159/000289201. Epub 2010 Feb 18. Review.
Duraisingham SS, Rouphael N, Cavanagh MM, Nakaya HI, Goronzy JJ, Pulendran B. Systems biology of vaccination in the elderly. Curr Top Microbiol Immunol. 2013;363:117-42. doi: 10.1007/82_2012_250. Review.
Public notes

Contacts
Principal investigator
Name 0 0
Katie Flanagan, PhD FRACP
Address 0 0
Clifford Craig Medical Research Trust
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Kathryn Ogden, MPH FRACGP
Address 0 0
Country 0 0
Phone 0 0
+61 3 6777 8790
Fax 0 0
Email 0 0
kathryn.ogden@utas.edu.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02765126