Dengue Vaccines: A Quick Overview

The rising tide of dengue has slowed down in Delhi as the temperatures have started to dip. In the mean time, Mexico has created a ripple by approving the use of Dengvaxia, a tetravalent vaccine against dengue a few days ago.

So, I was drawing up a summary of the different vaccines in play, and decided to post the list here. I am copy-pasting from an MS Word document and that may cause the formatting to go a bit wonky, pardon that!

Candidate Details of Vaccine Experimental Stage Efficiency etc. Time Horizon

CYD-TDV

Manufactured by Sanofi Pasteur

Tetravalent chimeric vaccine, developed using recombinant DNA technology; PrM (pre-membrane) and E (envelope) structural genes of the yellow fever 17D attenuated strain replaced by those from each of the four dengue serotypes. (1,2) Live attenuated vaccine. Phase III trials in Latin America and Asia are going on. Latin America study: (Columbia, Brazil, Mexico, Honduras, Puerto Rico)

Per protocol analysis shows vaccine efficacy of 60.8% (95% confidence interval [CI], 52.0 to 68.0). Intention to treat analysis showed efficacy of 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. (3)

Asian Study: (Indonesia, Malaysia, Phillipines, Viet Nam, Thailand)

Per protocol analysis showed vaccine efficacy was 56·5% (95% CI 43·8–66·4). Intention to treat analysis showed efficacy of 54.8% ( 95% CI 46.8-61.7). Serotype-specific vaccine efficacy was 50% (24.6-66.8) for serotype 1, 35% (-9.2-61) for serotype 2, 78.4% (52.9-90.8) for serotype 3, and 75.3% (54.5-87) for serotype 4. Unserotyped samples showed efficacy of 66.7% (-190.3-97.2).

(4)

Pooled Efficacy Analyses:

Vaccine efficacies against dengue in participants who were 9 years of age or older were similar in the individual trials, with a pooled estimate of 65.6% (95% CI, 60.7 to 69.9), as compared with 44.6% (95% CI, 31.6 to 55.0) among participants under the age of 9 years. Pooled serotype-specific vaccine efficacy was 58.4% (47.7-66.9) for serotype 1, 47.1% (31.3-59.2) for serotype 2, 73.6% (64.4-80.4) for serotype 3, and 83.2% (76.2-88.2) for serotype 4.(5)

The WHO Strategic Advisory Group of Experts (SAGE) in Immunization is likely to advise on the recommendations related to the use of a dengue vaccine in April 2016. (6) This vaccine is the farthest along the development process. Vaccines against dengue form one of the important strategies adopted by the WHO in its global vision to control dengue. (7)

Den-Vax

Manufactured by Takeda.

Recombinant chimeric vaccine with DEN1, DEN3 and DEN4 components on an attenuated DEN2 virus, the DEN2 PDK53. This tetravalent vaccine contains the prM and E genes of DEN-1, DEN-3 or DEN-4 virus in the genetic backbone of the DEN-2 PDK-53 virus. (8)

Live attenuated vaccine.

Phase II studies are ongoing in United States, Colombia, Puerto Rico, Singapore and Thailand. Dose escalation Phase I studies have shown acceptable tolerability and immunogenicity of the tetravalent vaccine in healthy, flavivirus naïve adults. (9) Phase II studies are ongoing; unlikely to result into an implementable product in the immediate future.

TV003/TV005

Manufactured by NIAID and Butantan Institute

Monovalent vaccine candidate strains are combined in different doses (five different combinations were made: TV001-TV005). Recently completed Phase I trials. Phase II studies ongoing in Brazil, Colombia, Thailand. The Brazil team (Butantan Institute) expects to initiate Phase III trials in 2016. A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. (10) Phase II studies are ongoing; unlikely to result into an implementable product in the immediate future.

TDENV PIV

Manufactured by Glaxo Smith Kline and Walter Reed Army Institute of Research.

Tetravalent, purified, inactivated vaccine with different adjuvants (aluminium hydroxide based). Recently completed Phase I trials. Phase I trials examining the safety and immunogenicity of the adjuvanted vaccines have shown that inactivated dengue vaccines, when formulated with alum or an Adjuvant System, are candidates for further development. (11) A prime boost strategy, combining the TDEN PIV and a live attenuated vaccine strain is currently in Phase II. (12) Phase II studies are ongoing; unlikely to result into an implementable product in the immediate future.

V180

Manufactured by Merck

Recombinant subunit vaccine based on the dengue wild type premembrane expression in Drosophila S2 cell expression system. (13) Phase I trials recently completed. Published results not available yet. n/a n/a

D1ME¹⁰⁰

Manufactured by the Naval Medical Research Center

Monovalent plasmid DNA vaccine. The premembrane and envelope proteins of DENV1 are expressed under control of the human cytomegalovirus promoter/enhancer of the plasmid vector VR1012. Phase I trials completed. But the results were not promising. Newer routes of delivery being explored for further Phase I investigation. (14) The vaccine was safe but there was noneutralizing antibody response to the low dose, and only 42% of par-ticipants with the high dose produced an antibody response that was not sustained long term. (15) n/a

VLP

Manufactured by ICGEB in India

DENV2 envelope expressed on yeast Pichia pastoralis. Proof of concept study published. Not clear if moving to Phase I trials. (16) n/a n/a

References

1. Yauch LE, Shresta S. Dengue virus vaccine development. Adv Virus Res [Internet]. 2014 Jan [cited 2015 Sep 13];88:315–72. Available from: http://www.sciencedirect.com/science/article/pii/B9780128000984000076
2. Thisyakorn U, Thisyakorn C. Latest developments and future directions in dengue vaccines. Ther Adv Vaccines [Internet]. SAGE Publications; 2013 Oct 15 [cited 2015 Oct 6];2(1):3–9. Available from: http://tav.sagepub.com/content/2/1/3.abstract
3. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med [Internet]. 2015 Jan 8 [cited 2015 Sep 23];372(2):113–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25365753
4. Capeding MR, Tran NH, Hadinegoro SRS, Ismail HIHM, Chotpitayasunondh T, Chua MN, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet [Internet]. 2014 Jul 11 [cited 2014 Jul 11];384(9951):1358–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25018116
5. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med [Internet]. 2015 Jul 27 [cited 2015 Jul 28];373(13):1195–206. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26214039
6. World Health Organization. SAGE Working Group on Dengue Vaccines and Vaccination [Internet]. Immunization, Vaccines and Biologicals. World Health Organization; 2015 [cited 2015 Oct 6]. p. 3. Available from: http://www.who.int/immunization/policy/sage/sage_wg_dengue_mar2015/en/
7. World Health Organization. Global Strategy for Dengue Prevention and Control 2012-2020. [Internet]. Geneva; 2012. Available from: http://apps.who.int/iris/bitstream/10665/75303/1/9789241504034_eng.pdf?ua=1
8. Osorio JE, Huang CY-H, Kinney RM, Stinchcomb DT. Development of DENVax: a chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever. Vaccine [Internet]. 2011 Sep 23 [cited 2015 Sep 11];29(42):7251–60. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4592106&tool=pmcentrez&rendertype=abstract
9. Osorio JE, Velez ID, Thomson C, Lopez L, Jimenez A, Haller AA, 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 [Internet]. Elsevier; 2014 Sep 9 [cited 2015 Oct 6];14(9):830–8. Available from: http://www.thelancet.com/article/S1473309914708114/fulltext
10. Kirkpatrick BD, Durbin AP, Pierce KK, Carmolli MP, Tibery CM, Grier PL, et al. Robust and Balanced Immune Responses to All 4 Dengue Virus Serotypes Following Administration of a Single Dose of a Live Attenuated Tetravalent Dengue Vaccine to Healthy, Flavivirus-Naive Adults. J Infect Dis [Internet]. 2015 Sep 1 [cited 2015 Oct 6];212(5):702–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25801652
11. Fernandez S, Thomas SJ, De La Barrera R, Im-Erbsin R, Jarman RG, Baras B, et al. An adjuvanted, tetravalent dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against dengue challenge in rhesus macaques. Am J Trop Med Hyg [Internet]. 2015 Apr [cited 2015 Oct 6];92(4):698–708. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4385761&tool=pmcentrez&rendertype=abstract
12. ClinicalTrials.gov. TDENV PIV and LAV Dengue Prime-boost Strategy [Internet]. U.S. National Institutes of Health. 2015 [cited 2015 Oct 6]. p. 3. Available from: https://clinicaltrials.gov/ct2/show/NCT02239614
13. Coller B-AG, Clements DE, Bett AJ, Sagar SL, Ter Meulen JH. The development of recombinant subunit envelope-based vaccines to protect against dengue virus induced disease. Vaccine [Internet]. 2011 Sep 23 [cited 2015 Oct 6];29(42):7267–75. Available from: http://www.sciencedirect.com/science/article/pii/S0264410X11010425
14. Schwartz LM, Halloran ME, Durbin AP, Longini IM. The dengue vaccine pipeline: Implications for the future of dengue control. Vaccine [Internet]. 2015 Jun 26 [cited 2015 Oct 6];33(29):3293–8. Available from: http://www.sciencedirect.com/science/article/pii/S0264410X15006313
15. Beckett CG, Tjaden J, Burgess T, Danko JR, Tamminga C, Simmons M, et al. Evaluation of a prototype dengue-1 DNA vaccine in a Phase 1 clinical trial. Vaccine [Internet]. 2011 Jan 29 [cited 2015 Oct 6];29(5):960–8. Available from: http://www.sciencedirect.com/science/article/pii/S0264410X10016841
16. Mani S, Tripathi L, Raut R, Tyagi P, Arora U, Barman T, et al. Pichia pastoris-expressed dengue 2 envelope forms virus-like particles without pre-membrane protein and induces high titer neutralizing antibodies. PLoS One [Internet]. Public Library of Science; 2013 Jan 23 [cited 2015 Oct 6];8(5):e64595. Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064595