Subdoses of 17DD yellow fever vaccine elicit equivalent virological/immunological kinetics timeline

Ana Carolina Campi-Azevedo, Paula de Almeida Estevam, Jordana Grazziela Coelho-Dos-Reis, Vanessa Peruhype-Magalhães, Gabriela Villela-Rezende, Patrícia Flávia Quaresma, Maria de Lourdes Sousa Maia, Roberto Henrique Guedes Farias, Luiz Antonio Bastos Camacho, Marcos da Silva Freire, Ricardo Galler, Anna Maya Yoshida Yamamura, Luiz Fernando Carvalho Almeida, Sheila Maria Barbosa Lima, Rita Maria Ribeiro Nogueira, Gloria Regina Silva Sá, Darcy Akemi Hokama, Ricardo de Carvalho, Ricardo Aguiar Villanova Freire, Edson Pereira Filho, Maria da Luz Fernandes Leal, Akira Homma, Andréa Teixeira-Carvalho, Reinaldo Menezes Martins, Olindo Assis Martins-Filho, Ana Carolina Campi-Azevedo, Paula de Almeida Estevam, Jordana Grazziela Coelho-Dos-Reis, Vanessa Peruhype-Magalhães, Gabriela Villela-Rezende, Patrícia Flávia Quaresma, Maria de Lourdes Sousa Maia, Roberto Henrique Guedes Farias, Luiz Antonio Bastos Camacho, Marcos da Silva Freire, Ricardo Galler, Anna Maya Yoshida Yamamura, Luiz Fernando Carvalho Almeida, Sheila Maria Barbosa Lima, Rita Maria Ribeiro Nogueira, Gloria Regina Silva Sá, Darcy Akemi Hokama, Ricardo de Carvalho, Ricardo Aguiar Villanova Freire, Edson Pereira Filho, Maria da Luz Fernandes Leal, Akira Homma, Andréa Teixeira-Carvalho, Reinaldo Menezes Martins, Olindo Assis Martins-Filho

Abstract

Background: The live attenuated 17DD Yellow Fever vaccine is one of the most successful prophylactic interventions for controlling disease expansion ever designed and utilized in larger scale. However, increase on worldwide vaccine demands and manufacturing restrictions urge for more detailed dose sparing studies. The establishment of complementary biomarkers in addition to PRNT and Viremia could support a secure decision-making regarding the use of 17DD YF vaccine subdoses. The present work aimed at comparing the serum chemokine and cytokine kinetics triggered by five subdoses of 17DD YF Vaccine.

Methods: Neutralizing antibody titers, viremia, cytokines and chemokines were tested on blood samples obtained from eligible primary vaccinees.

Results and discussion: The results demonstrated that a fifty-fold lower dose of 17DD-YF vaccine (587 IU) is able to trigger similar immunogenicity, as evidenced by significant titers of anti-YF PRNT. However, only subdoses as low as 3,013 IU elicit viremia kinetics with an early peak at five days after primary vaccination equivalent to the current dose (27,476 IU), while other subdoses show a distinct, lower in magnitude and later peak at day 6 post-vaccination. Although the subdose of 587 IU is able to trigger equivalent kinetics of IL-8/CXCL-8 and MCP-1/CCL-2, only the subdose of 3,013 IU is able to trigger similar kinetics of MIG/CXCL-9, pro-inflammatory (TNF, IFN-γ and IL-2) and modulatory cytokines (IL-5 and IL-10).

Conclusions: The analysis of serum biomarkers IFN-γ and IL-10, in association to PRNT and viremia, support the recommendation of use of a ten-fold lower subdose (3,013 IU) of 17DD-YF vaccine.

Figures

Figure 1
Figure 1
Flowchart illustrating the study population and experimental design. The study was organized in four phases: Screening, Sampling, Grouping and Design. “Screening” of volunteers was performed taking into account: i) missing blood collection at baseline (n = 50); ii) insufficient sample volume (n = 147); iii) seropositivity at baseline (n = 75) and iv) timeline interval of blood collection >34 days and <365 days after primary vaccination (n = 37). The eligible population comprises 590 primovaccinees. “Sampling” consisted of either two (n = 295) or three (n = 295) blood collections. The serum samples were paired to their respective sample collected at baseline, resulting in a total of 885 baseline-paired samples. “Grouping” was performed according to the dose of 17DD YF vaccine administered (27,476 IU; 10,447 IU; 3,013 IU; 587 IU; 158 IU and 31 IU). Paired samples were further subcategorized according and the timepoint (days) in which the sample was collected (Baseline; D3; D4; D5; D5; D7(7–12); D15(13–25) and D30(26–34). A final blood collection of these volunteers was taken at 365 days after primary vaccination (n = 555) to monitor anti-YF antibody status. “Design” included: i) PRNT assays performed at baseline, D30 and D365; ii) Viremia quantified at D3, D4, D5, D6 and D7 and iii) Kinetics of serum chemokines and cytokines evaluated from baseline to D30.
Figure 2
Figure 2
Immunogenicity and Viremia kinetics following 17DD-YF primary vaccination with different doses (27,476 IU-current; 10,447 IU; 3,013 IU; 587 IU; 158 IU and 31 IU). (A) Anti-YF neutralizing antibody titers (• = current dose and fades for subdoses) were measured by PRNT assay carried out 26–34 days (D30) after primary vaccination, as described in Methods. PRNT antibody titers are expressed in log10 mIU/mL and 2.7 log10 mIU/mL as the cut-off point to segregate seropositive from seronegative samples. Significant seropositivy rates (>95%) are highlighted by gray rectangle. (B) Viremia ( = current dose and fades for subdoses) was quantified by Real-time PCR at D3, D4, D5, D6 and D7 after primary vaccination as described in Methods. Viremia results are expressed in copies/mL. Kinetics profiles equivalent to current dose (27,476 IU) are highlighted by gray rectangle. The peaks of fold changes along the timeline were also taken into account as a relevant feature for equivalence assessment and highlighted by *.
Figure 3
Figure 3
Kinetics of serum chemokines following 17DD-YF primary vaccination with different doses (27,476 IU-current; 10,447 IU; 3,013 IU; 587 IU; 158 IU and 31 IU). Serum levels of IL-8/CXCL-8 (), MCP-1/CCL-2 (), MIG/CXCL-9 () and IP-10/CXCL-10 () were measured by cytometric beads array (CBA) as described in Methods. The colors assigned for the current dose fade away for subdoses. Results are expressed as baseline fold change of each timepoint (Serum level/D0). Kinetics profiles equivalent to current dose (27,476 IU) are highlighted by gray rectangle. The peaks of fold changes along the timeline were also taken into account as a relevant feature for equivalence assessment and highlighted by *.
Figure 4
Figure 4
Kinetics of pro-inflammatory cytokines following 17DD-YF primary vaccination with different doses (27,476 IU-current; 10,447 IU; 3,013 IU; 587 IU; 158 IU and 31 IU). Serum levels of the pro-inflammatory cytokines TNF (), IFN-γ () and IL-2 () were measured by cytometric beads array (CBA) as described in Methods. The colors assigned for the current dose fade away for subdoses. Results are expressed as baseline fold change of each timepoint (Serum level/D0). Kinetics profiles equivalent to current dose (27,476 IU) are highlighted by gray rectangle. The peaks of fold changes along the timeline were also taken into account as a relevant feature for equivalence assessment and highlighted by *.
Figure 5
Figure 5
Kinetics of regulatory cytokines following 17DD-YF primary vaccination with different doses (27,476 IU-current; 10,447 IU; 3,013 IU; 587 IU; 158 IU and 31 IU). Serum levels of the regulatory cytokines IL-4 (), IL-5 () and IL-10 () were measured by cytometric beads array (CBA) as described in Methods. The colors assigned for the current dose fade away for subdoses. Results are expressed as baseline fold change of each timepoint (Serum level/D0). Kinetics profiles equivalent to current dose (27,476 IU) are highlighted by gray rectangle. The peaks of fold changes along the timeline were also taken into account as a relevant feature for equivalence assessment and highlighted by *.
Figure 6
Figure 6
Snapshot of immunological and virological biomarkers following 17DD-YF primary vaccination with different doses (27,476 IU-current; 10,447 IU; 3,013 IU; 587 IU; 158 IU and 31 IU). (A) Selection of biomarkers with equivalent kinetics timeline with viremia and PRNT [Viremia (); PRNT (); IL-8/CXCL-8 (); MCP-1/CCL-2 (); MIG/CXCL-9 (); IP-10/CXCL-10 (); TNF (), IFN-γ () and IL-2 ();IL-4 (), IL-5 () and IL-10 ()]. (B) Overlay graphs highlighting that IFN-γ and IL-10 are relevant complementary biomarkers associated with the viremia kinetics. Results are expressed as the global maximum values of each timepoint to baseline (viremia, , range 0 to 1.6E + 04 copies/mL; INF-γ, , range 0 to 4 baseline fold; IL-10, , range 0 to 2 baseline fold).

References

    1. Vasconcelos PF. Yellow fever. Rev Soc Bras Med Trop. 2003;36(2):275–293. doi: 10.1590/S0037-86822003000200012.
    1. Tomori O. Yellow fever: the recurring plague. Crit Rev Clin Lab Sci. 2004;41(4):391–427. doi: 10.1080/10408360490497474.
    1. Gubler DJ. The global resurgence of arboviral diseases. Trans R Soc Trop Med Hyg. 1996;90(5):449–451. doi: 10.1016/S0035-9203(96)90286-2.
    1. Pulendran B. Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology. Nat Rev Immunol. 2009;9(10):741–747.
    1. (WHO) WHO. Bolletin Requirements for Biological Substances. Geneve: WHO; 2008. Expert Committee on Biological Standardization: Requirements for yellow fever vaccine.
    1. (WHO) WHO. Searchable Database of WHO Pre Qualified Vaccines. WHO; 2014. Accessed 10 of July 2014. Date of last revision of vaccine list: 01 April 2014.
    1. Camacho LA. Yellow fever and public health in Brazil. Cad Saude Publica. 2008;24(3):482–483. doi: 10.1590/S0102-311X2008000300001.
    1. Freire MS, Mann GF, Marchevsky RS, Yamamura AM, Almeida LF, Jabor AV, Malachias JM, Coutinho ES, Galler R. Production of yellow fever 17DD vaccine virus in primary culture of chicken embryo fibroblasts: yields, thermo and genetic stability, attenuation and immunogenicity. Vaccine. 2005;23(19):2501–2512. doi: 10.1016/j.vaccine.2004.10.035.
    1. Martins RM, Maia Mde L, Farias RH, Camacho LA, Freire MS, Galler R, Yamamura AM, Almeida LF, Lima SM, Nogueira RM, Sá GR, Hokama DA, de Carvalho R, Freire RA, Pereira Filho E, Leal Mda L, Homma A. 17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose–response study. Hum Vaccin Immunother. 2013;9(4):879–888. doi: 10.4161/hv.22982.
    1. Lopes Ode S, Guimaraes SS, de Carvalho R. Studies on yellow fever vaccine. III–dose response in volunteers. J Biol Stand. 1988;16(2):77–82. doi: 10.1016/0092-1157(88)90034-0.
    1. Stefano I, Sato HK, Pannuti CS, Omoto TM, Mann G, Freire MS, Yamamura AM, Vasconcelos PF, Oselka GW, Weckx LW, Salgado MF, Noale LF, Souza VA. Recent immunization against measles does not interfere with the sero-response to yellow fever vaccine. Vaccine. 1999;17(9–10):1042–1046.
    1. Mantel N, Aguirre M, Gulia S, Girerd-Chambaz Y, Colombani S, Moste C, Barban V. Standardized quantitative RT-PCR assays for quantitation of yellow fever and chimeric yellow fever-dengue vaccines. J Virol Methods. 2008;151(1):40–46. doi: 10.1016/j.jviromet.2008.03.026.
    1. Chao DY, Davis BS, Chang GJ. Development of multiplex real-time reverse transcriptase PCR assays for detecting eight medically important flaviviruses in mosquitoes. J Clin Microbiol. 2007;45(2):584–589. doi: 10.1128/JCM.00842-06.
    1. Peruhype-Magalhaes V, Martins-Filho OA, Prata A, Silva Lde A, Rabello A, Teixeira-Carvalho A, Figueiredo RM, Guimaraes-Carvalho SF, Ferrari TC, Van Weyenbergh J, Correa-Oliveira R. Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-gamma and interleukin-10 and low frequency of tumour necrosis factor-alpha(+) monocytes are hallmarks of active human visceral Leishmaniasis due to Leishmania chagasi infection. Clin Exp Immunol. 2006;146(1):124–132. doi: 10.1111/j.1365-2249.2006.03171.x.
    1. Ahmed R, Pulendran B. Learning vaccinology from viral infections. J Exp Med. 2011;208(12):2347–2349. doi: 10.1084/jem.20112321.
    1. Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, Akira S, Ahmed R, Pulendran B. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med. 2006;203(2):413–424. doi: 10.1084/jem.20051720.
    1. Martins MA, Silva ML, Marciano AP, Peruhype-Magalhaes V, Eloi-Santos SM, Ribeiro j G, Correa-Oliveira R, Homma A, Kroon EG, Teixeira-Carvalho A, Martins-Filho OA. Activation/modulation of adaptive immunity emerges simultaneously after 17DD yellow fever first-time vaccination: is this the key to prevent severe adverse reactions following immunization? Clin Exp Immunol. 2007;148(1):90–100. doi: 10.1111/j.1365-2249.2006.03317.x.
    1. Silva ML, Martins MA, Espirito-Santo LR, Campi-Azevedo AC, Silveira-Lemos D, Ribeiro JG, Homma A, Kroon EG, Teixeira-Carvalho A, Eloi-Santos SM, Martins-Filho OA. Characterization of main cytokine sources from the innate and adaptive immune responses following primary 17DD yellow fever vaccination in adults. Vaccine. 2011;29(3):583–592. doi: 10.1016/j.vaccine.2010.08.046.
    1. Ravindran R, Khan N, Nakaya HI, Li S, Loebbermann J, Maddur MS, Park Y, Jones DP, Chappert P, Davoust J, Weiss DS, Virgin HW, Ron D, Pulendran B. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science. 2014;343(6168):313–317. doi: 10.1126/science.1246829.
    1. Campi-Azevedo AC, de Araujo-Porto LP, Luiza-Silva M, Batista MA, Martins MA, Sathler-Avelar R, da Silveira-Lemos D, Camacho LA, de Menezes MR, de Lourdes de Sousa Maia M, Farias RH, da Silva Freire M, Galler R, Homma A, Ribeiro JG, Lemos JA, Auxiliadora-Martins M, Caldas IR, Elói-Santos SM, Teixeira-Carvalho A, Martins-Filho OA. 17DD and 17D-213/77 yellow fever substrains trigger a balanced cytokine profile in primary vaccinated children. PLoS ONE. 2012;7(12):e49828. doi: 10.1371/journal.pone.0049828.
    1. Akondy RS, Monson ND, Miller JD, Edupuganti S, Teuwen D, Wu H, Quyyumi F, Garg S, Altman JD, Del Rio C, Keyserling HL, Ploss A, Rice CM, Orenstein WA, Mulligan MJ, Ahmed R. The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J Immunol. 2009;183(12):7919–7930. doi: 10.4049/jimmunol.0803903.
    1. Luiza-Silva M, Campi-Azevedo AC, Batista MA, Martins MA, Avelar RS, da Silveira LD, Bastos Camacho LA, de Menezes MR, de Lourdes de Sousa Maia M, Guedes Farias RH, da Silva Freire M, Galler R, Homma A, Leite Ribeiro JG, Campos Lemos JA, Auxiliadora-Martins M, Eloi-Santos SM, Teixeira-Carvalho A, Martins-Filho OA. Cytokine signatures of innate and adaptive immunity in 17DD yellow fever vaccinated children and its association with the level of neutralizing antibody. J Infect Dis. 2011;204(6):873–883. doi: 10.1093/infdis/jir439.
    1. Jonsson N, Gullberg M, Lindberg AM. Real-time polymerase chain reaction as a rapid and efficient alternative to estimation of picornavirus titers by tissue culture infectious dose 50% or plaque forming units. Microbiol Immunol. 2009;53(3):149–154. doi: 10.1111/j.1348-0421.2009.00107.x.

Source: PubMed

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