Citation: Deen J (2016) The Dengue Vaccine Dilemma: Balancing the Individual and Population Risks and Benefits. PLoS Med 13(11): e1002182. https://doi.org/10.1371/journal.pmed.1002182
Published: November 29, 2016
Copyright: © 2016 Jacqueline Deen. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: No funding was received for this work.
Competing interests: I have read the journal's policy and have the following conflicts: I was an unpaid external consultant in the "Extended Study Group for dengue vaccine effectiveness evaluation studies in Asia” from 6 April 2015 to 31 August 2015 convened by Sanofi Pasteur. I was a WHO temporary adviser in a meeting entitled “Targeting Vaccination and Post-licensure Studies for the Licensed Dengue Vaccine” in Geneva from 14 to 15 June 2016 convened by the WHO. I am an unpaid co-investigator of a study entitled “Effectiveness of the tetravalent dengue vaccine, CYD-TDV (Dengvaxia) in the Philippines” currently in preparation, sponsored by the University of the Philippines-Manila and funded by Sanofi Pasteur.
Abbreviations: IgG, immunoglobulin G; PRNT, plaque reduction neutralization test; SAGE, Strategic Advisory Group of Experts
Provenance: Commissioned; not externally peer reviewed
In tropical Asia and Latin America, dengue is a significant public health threat. Several characteristics of the disease contribute to this high sense of priority, including its geographic spread, lack of specific treatment other than supportive therapy, and the burden it imposes on clinics and hospitals. In hyperendemic areas with circulation of the four dengue serotypes, recurrent dengue infections are common. Primary infection is generally asymptomatic or manifests as self-limiting dengue fever, whereas there is an increased risk of severe dengue during secondary infection . The most prominent feature of severe dengue (previously called dengue hemorrhagic fever and dengue shock syndrome) is a transient increase in vascular permeability, resulting in plasma leakage that may lead to circulatory compromise, shock, and death . Coagulation abnormalities, hepatitis, renal failure, myocarditis, or encephalitis may also occur. Postsecondary infections are associated with a reduced risk of disease .
Wide-scale dengue vaccination would represent a major advance in the control of the disease, but dengue vaccine development has been slow and difficult . Vaccine development is hindered by the complex immune response to the dengue virus and the difficulty in eliciting concomitant protection against its antigenically distinct serotypes. CYD-TDV (Dengvaxia, Sanofi Pasteur) is the first dengue vaccine to become available, but it arrives with a complex set of challenges .
The CYD-TDV vaccine consists of four chimeric viruses made by replacing the premembrane and envelope structural genes of the attenuated yellow fever 17D vaccine strain with the corresponding genes from each of the four dengue serotypes . CYD-TDV is administered subcutaneously as a primary dose followed by subsequent doses 6 and 12 months later. Large Phase III trials were conducted among 2 to 14 year olds in five Asian countries  and 9 to 16 year olds in five Latin American countries . In pooled analysis of follow-up to 25 months after the first dose, vaccine efficacy against symptomatic dengue was 60% for all participants, 66% for those 9 years of age or older, and 45% for those younger than 9 years of age . Importantly, among the Asian children vaccinated at ages 2 to 5 years, a statistically significant increased risk of hospitalized dengue was seen in the vaccine recipients. Subgroup analysis showed higher rates of protection among participants who were already seropositive prior to vaccination (i.e., partially dengue immune) compared to those who were not. CYD-TDV has been licensed in Paraguay, Mexico, Brazil, El Salvador, Costa Rica, and the Philippines for use in preadolescents, adolescents and adults from 9 to 60 years of age living in dengue-endemic areas .
The World Health Organization convened a Strategic Advisory Group of Experts (SAGE) who reviewed the evidence and recommended that countries consider introduction of the vaccine only in settings with high endemicity, defined by a seroprevalence of at least 70% in the target age group . The experts advised not to use the vaccine in populations with seroprevalence <50%. The seroprevalence threshold was based on the modeling study published in this week’s PLOS Medicine, which used the assumption that CYD-TDV vaccination immunologically primes seronegative recipients, causing their first natural dengue infection to have higher severity, like that seen with secondary infection in unvaccinated persons . The mathematical model predicts the greatest impact in a high endemicity setting where routine vaccination of 9 year olds at 80% coverage would reduce dengue-related hospitalizations by 13% to 25% over 30 years. In contrast, vaccination in low-transmission settings with a high population of seronegatives will increase the number of hospitalized dengue cases [11,12].
The WHO recommendations have split the dengue community into those that support [13,14] and challenge [15,16] them. In theory, wide deployment of CYD-TDV within the recommended populations could result in considerable public health benefit. But what of the seronegative individuals who are vaccinated and become at increased risk for severe disease? It has been argued that in high-transmission settings, CYD-TDV vaccination simply accelerates the natural progression of dengue disease acquisition by the population. That is, even if CYD-TDV primes seronegative individuals for a secondary-like infection associated with more severe disease, unvaccinated seronegative individuals would similarly experience secondary infections because of a high level of exposure . If policymakers accept this argument and the decision to rollout CYD-TDV is made, how can this be done? Identifying the population that would benefit most is important not only to limit the negative impact of vaccination of seronegatives but also to ensure cost-effectiveness. Vaccination of populations who have already experienced secondary and tertiary dengue infections would be a waste of resources. Rational decision making requires reliable seroprevalence data, which are not easy to come by. Seroprevalence surveys are time-consuming, expensive, require technical expertise and their results are dynamic. The plaque reduction neutralization test (PRNT) is the most widely accepted approach for detecting and measuring dengue antibodies, but it is cumbersome, not widely available, and compromised by several limitations, including a wide variation in titer results in response to different testing conditions [17,18]. Simpler serological tests would be more practical but require further validation for this purpose. Other markers of dengue prevalence that rely on routine surveillance, such as mean dengue hospitalization age, are more accessible but of little use, as the relationship between this indicator and the optimal age of vaccination is not known. Individual screening using a simple, indirect dengue immunoglobulin G (IgG) test prior to immunization has been recommended . Although this strategy may be feasible in some countries or in the private sector, the SAGE experts did not consider this approach generally advisable because of the limitations of available tests and logistical challenges .
Earlier this year, the Philippines launched a pilot project to vaccinate nine-year-old children in public schools in three regions of the country . Brazil just announced a dengue vaccination program in the southern state of Paraná . This slow rollout of CYD-TDV is far from the enthusiastic uptake expected when a dengue vaccine would finally become available . There is no question that a dengue vaccine is urgently needed, but countries are justifiably cautious of CYD-TDV.
The current debate surrounding CYD-TDV use highlights the urgent need for a better dengue vaccine. Of the dengue vaccine candidates, two are furthest along in clinical development . The Takeda tetravalent dengue vaccine has completed a Phase II clinical trial in Puerto Rico, Colombia, Singapore, and Thailand  and is currently undergoing a multicountry Phase III evaluation . The attenuated tetravalent lyophilized dengue vaccine developed by the United States National Institutes of Health and National Institute of Allergy and Infectious Diseases and manufactured by Butantan Institute has completed Phase I and II studies [25,26], and a Phase III  study is currently underway. Several other dengue vaccine candidates are in preclinical development. There remains hope that a dengue vaccine that confers simultaneous protection against all dengue serotypes will become available one day.
- 1. Simmons CP, Farrar JJ, Nguyen VV, Wills B (2012) Dengue. N Engl J Med 366: 1423–1432. pmid:22494122
- 2. WHO/TDR (2009) Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. Geneva.
- 3. Olkowski S, Forshey BM, Morrison AC, Rocha C, Vilcarromero S, et al. (2013) Reduced risk of disease during postsecondary dengue virus infections. J Infect Dis 208: 1026–1033. pmid:23776195
- 4. Thomas SJ, Rothman AL (2015) Trials and Tribulations on the Path to Developing a Dengue Vaccine. Am J Prev Med 49: S334–344. pmid:26590433
- 5. Halstead SB (2016) Licensed Dengue Vaccine: Public Health Conundrum and Scientific Challenge. Am J Trop Med Hyg 95: 741–745. pmid:27352870
- 6. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, et al. (2014) 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 384: 1358–1365. pmid:25018116
- 7. Villar L, Dayan GH, Arredondo-Garcia JL, Rivera DM, Cunha R, et al. (2015) Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 372: 113–123. pmid:25365753
- 8. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, et al. (2015) Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med 373: 1195–1206. pmid:26214039
- 9. Sanofi Pasteur. Dengue Vaccine Approved in Paraguay to Strengthen Dengue Burden Reduction Efforts in Southern Cone. 2016. http://www.sanofipasteur.com/en/Documents/PDF/PR-locaux/Paraguay_RegistraVacunaContraElDengueSanofiPasteur-ENGLISH_rev15_08_2016.pdf Cited 14 October 2016.
- 10. WHO (2016) Meeting of the Strategic Advisory Group of Experts on immunization, April 2016—conclusions and recommendations. Wkly Epidemiol Rec 91: 266–284. pmid:27236869
- 11. Flasche S, Jit M, Rodríguez-Barraquer I, Coudeville L, Recker M, Koelle K, et al. (2016) The long-term safety, public health impact, and cost-effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study. PLoS Med 13(11):e1002181
- 12. Ferguson NM, Rodriguez-Barraquer I, Dorigatti I, Mier YT-RL, Laydon DJ, et al. (2016) Benefits and risks of the Sanofi-Pasteur dengue vaccine: Modeling optimal deployment. Science 353: 1033–1036. pmid:27701113
- 13. Pang T (2016) SAGE committee advice on dengue vaccine. Lancet Infect Dis 16: 880–882. pmid:27477966
- 14. Wilder-Smith A, Vannice KS, Hombach J, Farrar J, Nolan T (2016) Population Perspectives and World Health Organization Recommendations for CYD-TDV Dengue Vaccine. J Infect Dis. E-pub ahead of print. pmid:27496977
- 15. Aguiar M, Stollenwerk N, Halstead SB (2016) The risks behind Dengvaxia recommendation. Lancet Infect Dis 16: 882–883. pmid:27477967
- 16. Halstead SB (2016) Critique of World Health Organization Recommendation of a Dengue Vaccine. J Infect Dis. E-pub ahead of print. pmid:27496975
- 17. Thomas SJ, Nisalak A, Anderson KB, Libraty DH, Kalayanarooj S, et al. (2009) Dengue plaque reduction neutralization test (PRNT) in primary and secondary dengue virus infections: How alterations in assay conditions impact performance. Am J Trop Med Hyg 81: 825–833. pmid:19861618
- 18. Sirivichayakul C, Sabchareon A, Limkittikul K, Yoksan S (2014) Plaque reduction neutralization antibody test does not accurately predict protection against dengue infection in Ratchaburi cohort, Thailand. Virol J 11: 48. pmid:24620925
- 19. Sanofi Pasteur. World’s First Public Dengue Immunization Program Starts in the Philippines. 2016. http://www.sanofipasteur.com/en/articles/World-s-First-Public-Dengue-Immunization-Program-Starts-in-the-Philippines.aspx Cited 14 October 2016.
- 20. Sanofi Pasteur. First dengue vaccination program in the Americas starts in Paraná State of Brazil. 2016. http://www.sanofipasteur.com/en/Documents/PDF/PR-locaux/BrazilParanastatelaunchdenguevaccine_multilocalPR_EN.pdf Cited 14 October 2016.
- 21. Douglas DL, DeRoeck DA, Mahoney RT, Wichmann O (2013) Will dengue vaccines be used in the public sector and if so, how? Findings from an 8-country survey of policymakers and opinion leaders. PLoS Negl Trop Dis 7: e2127. pmid:23516658
- 22. Schwartz LM, Halloran ME, Durbin AP, Longini IM Jr. (2015) The dengue vaccine pipeline: Implications for the future of dengue control. Vaccine 33: 3293–3298. pmid:25989449
- 23. Sirivichayakul C, Barranco-Santana EA, Esquilin-Rivera I, Oh HM, Raanan M, et al. (2016) 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 213: 1562–1572. pmid:26704612
- 24. ClinicalTrials.gov Identifier: NCT02747927 https://clinicaltrials.gov/ct2/show/NCT02747927 Cited 14 October 2016.
- 25. Kirkpatrick BD, Durbin AP, Pierce KK, Carmolli MP, Tibery CM, et al. (2015) 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 212: 702–710. pmid:25801652
- 26. ClinicalTrials.gov Identifier: NCT01696422 https://clinicaltrials.gov/ct2/show/NCT01696422 Cited 14 October 2016.
- 27. ClinicalTrials.gov Identifier: NCT02406729 https://clinicaltrials.gov/ct2/show/NCT02406729 Cited 14 October 2016.