Immunogenicity and safety of lyophilized and liquid dengue tetravalent vaccine candidate formulations in healthy adults: a randomized, phase 2 clinical trial

Mark Turner, Athanasia Papadimitriou, Peter Winkle, Nathan Segall, Michael Levin, Matthew Doust, Casey Johnson, Gregg Lucksinger, Carlos Fierro, Paul Pickrell, Marsha Raanan, Vianney Tricou, Astrid Borkowski, Derek Wallace, Mark Turner, Athanasia Papadimitriou, Peter Winkle, Nathan Segall, Michael Levin, Matthew Doust, Casey Johnson, Gregg Lucksinger, Carlos Fierro, Paul Pickrell, Marsha Raanan, Vianney Tricou, Astrid Borkowski, Derek Wallace

Abstract

Takeda has developed a live-attenuated dengue tetravalent vaccine candidate (TAK-003) which has been shown to be immunogenic with acceptable reactogenicity in phase 1 trials. In agreement with World Health Organization prequalification requirements for dengue vaccines, Takeda has manufactured a lyophilized formulation of TAK-003 that allows stable storage at +2°C to +8°C. This randomized, double-blind, phase 2 study (NCT02193087) was performed in 1002 healthy dengue-naïve adults, 18-49 years of age, across seven centers in the USA to compare the safety and immunogenicity of one or two doses of a lyophilized TAK-003 formulation with the liquid TAK-003 formulation used in previous phase 1 studies. The primary objective was to show immunologic equivalence in terms of geometric mean titers (GMT) of neutralizing antibodies to the four dengue serotypes one month after one dose of the lyophilized and liquid formulations. Secondary assessments were of safety and seropositivity rates, including after a second dose. The primary endpoint was not met, because immunologic equivalence after one dose was only shown for the DENV-2 serotype. Nonetheless, GMTs and seropositivity rates to all four serotypes were achieved with all formulations after two doses and are in line with what was observed in previous studies. Additionally, in view of the acceptable reactogenicity, with no vaccine-related serious adverse events reported, these data support continuing further clinical development of the lyophilized TAK-003 formulation.

Keywords: Dengue; Takeda; adults; tetravalent; vaccine.

Figures

Figure 1.
Figure 1.
Study design and subject disposition
Figure 2.
Figure 2.
Geometric Mean Titers (GMTs) of serotype-specific antibodies (with 90% CI bars) at baseline and 30, 90, and 120 days after administration of the first vaccine dose (Per Protocol set)
Figure 3.
Figure 3.
Serotype-specific seropositivity rates (with 90% CI bars) 30 days after administration of first (Day 30) and second (Day 120) vaccine doses (Per Protocol set)
Figure 4.
Figure 4.
Percentages of subjects experiencing solicited local reactions within 7 days of vaccination (safety analysis set). Severe pain defined as significant pain at rest, or pain preventing normal activity. Severe erythema or swelling defined as >10 cm

References

    1. Guzman MG, Harris E.. Dengue. Lancet. 2015;385:453–65. doi:10.1016/S0140-6736(14)60572-9.
    1. Dengue vaccine: WHO position paper - July 2016.World Health Organization.Wkly Epidemiol Rec. 2016;91:349–64.
    1. Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, Moyes CL, Farlow AW, Scott TW, Hay SI, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012;6:e1760. doi:10.1371/journal.pntd.0001760.
    1. Beatty ME, Beutels P, Meltzer MI, Shepard DS, Hombach J, Hutubessy R, Dervaux B, Wichmann O, Meltzer MI, Kuritsky JN, et al. Health economics of dengue: a systematic literature review and expert panel’s assessment. Am J Trop Med Hyg. 2011;84:473–88. doi:10.4269/ajtmh.2011.10-0521.
    1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, et al. The global distribution and burden of dengue. Nature. 2013;496:504–07. doi:10.1038/nature12060.
    1. Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, Coffeng LE, Brady OJ, Hay SI, Bedi N, Bensenor IM, Castañeda-Orjuela CA, et al. The global burden of dengue: an analysis from the global burden of disease study 2013. Lancet Infect Dis. 2016;16:712–23. doi:10.1016/S1473-3099(16)00026-8.
    1. World Health Organization . Dengue guidelines for diagnosis, treatment, prevention and control: new edition. Geneva (Switzerland); 2009. accessed 2020 January7. .
    1. Guzman MG, Alvarez M, Halstead SB. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol. 2013;158:1445–59. doi:10.1007/s00705-013-1645-3.
    1. World Health Organization . Dengue and severe dengue. April 2019. [accessed 2020 January7]. .
    1. World Health Organization . Policy recommendations on the use of the first licensed dengue vaccine. Weekly Epidemiol Rec. 2018;93:337–40.
    1. Osorio JE, Huang CY, Kinney RM, Stinchcomb DT. Development of DENVax: a chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever. Vaccine. 2011;29:7251–60. doi:10.1016/j.vaccine.2011.07.020.
    1. George SL, Wong MA, Dube TJ, Boroughs KL, Stovall JL, Luy BE, Haller AA, Osorio JE, Eggemeyer LM, Irby-Moore S, et al. Safety and immunogenicity of a live attenuated tetravalent dengue vaccine candidate in flavivirus-naive adults: a randomized, double-blinded phase 1 clinical trial. J Infect Dis. 2015;212:1032–41. doi:10.1093/infdis/jiv179.
    1. Osorio JE, Velez ID, Thomson C, Lopez L, Jimenez A, Haller AA, Silengo S, Scott J, Boroughs KL, Stovall JL, et al. Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study. Lancet Infect Dis. 2014;14:830–38. doi:10.1016/S1473-3099(14)70811-4.
    1. Rupp R, Luckasen GJ, Kirstein JL, Osorio JE, Santangelo JD, Raanan M, Smith MK, Wallace D, Gordon GS, Stinchcomb DT, et al. Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: a Phase 1b randomized study. Vaccine. 2015;33:6351–59. doi:10.1016/j.vaccine.2015.09.008.
    1. Sirivichayakul C, Barranco-Santana EA, Esquilin-Rivera I, Oh HML, Raanan M, Sariol CA, Shek LP, Simasathien S, Smith MK, Velez ID, et al. Safety and immunogenicity of a tetravalent dengue vaccine candidate in healthy children and adults in dengue-endemic regions: a randomized, placebo-controlled phase 2 study. J Infect Dis. 2016;213:1562–72. doi:10.1093/infdis/jiv762.
    1. Jackson LA, Rupp R, Papadimitriou A, Wallace D, Raanan M, Mosse KJ. A phase 1 study of safety and immunogenicity following intradermal administration of a tetravalent dengue vaccine candidate. Vaccine. 2018;36:3976–83. doi:10.1016/j.vaccine.2018.05.028.
    1. World Health Organization . Assessing the programmatic suitability of vaccine candidates for WHO prequalification - revision 2014. Geneva (Switzerland); 2015. accessed 2020 January7. .
    1. Roehrig JT, Hombach J, Barrett AD. Guidelines for plaque-reduction neutralization testing of human antibodies to dengue viruses. Viral Immunol. 2008;21:123–32. doi:10.1089/vim.2008.0007.
    1. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15:657–80. doi:10.1007/BF01068419.
    1. Tricou V, Low JG, Oh HM, Leo YS, Kalimuddin S, Wijaya L, Pang J, Ling LM, Lee TH, Brose M, et al. Safety and immunogenicity of a single dose of a tetravalent dengue vaccine with two differentserotype-2 potencies in adults in Singapore: A phase 2, double-blind, randomised, controlled trial. Vaccine. 2019. doi:10.1016/j.vaccine.2019.11.061.
    1. Saez-Llorens X, Tricou V, Yu D, Rivera L, Tuboi S, Garbes P, Borkowski A, Wallace D. Safety and immunogenicity of one versus two doses of Takeda’s tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study. Lancet Infect Dis. 2017;17:615–25. doi:10.1016/S1473-3099(17)30166-4.
    1. Saez-Llorens X, Tricou V, Yu D, Rivera L, Jimeno J, Villarreal AC, Dato E, Mazara S, Vargas M, Brose M, et al. Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2–17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study. Lancet Infect Dis. 2018;18:162–70. doi:10.1016/S1473-3099(17)30632-1.
    1. Biswal S, Reynales H, Saez-Llorens X, Lopez P, Borja-Tabora C, Kosalaraksa P, Sirivichayakul C, Watanaveeradej V, Rivera L, Espinoza F, et al. Efficacy of a tetravalent dengue vaccine in healthy children and adolescents. N Engl J Med. 2019;381:2009–19. doi:10.1056/NEJMoa1903869.
    1. Chu H, George SL, Stinchcomb DT, Osorio JE, Partidos CD. CD8+ T-cell responses in flavivirus-naive individuals following immunization with a live-attenuated tetravalent dengue vaccine candidate. J Infect Dis. 2015;212:1618–28. doi:10.1093/infdis/jiv258.
    1. Osorio JE, Wallace D, Stinchcomb DT. A recombinant, chimeric tetravalent dengue vaccine candidate based on a dengue virus serotype 2 backbone. Expert Rev Vaccines. 2016;15:497–508. doi:10.1586/14760584.2016.1128328.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir