1
PERSPECTIVE
Dengue Vaccines for Travelers: Has the Time Come? Annelies Wilder-Smith, MD, PhD Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore DOI: 10.1111/jtm.12198
T
he need for a dengue vaccine is more pressing than ever, both for the endemic population and for international travelers.1,2 The recent completion of two efficacy trials for the live attenuated chimeric dengue vaccine in 20143,4 may signify the dawn of a new era in dengue control in dengue-endemic countries.5 Does it also signify a new era for dengue prevention in international travelers? To answer this question, it is important to first summarize the main findings from these two phase 3 trials evaluating a dengue vaccine that has to date gone furthest in development: the recombinant, live, attenuated, tetravalent vaccine developed by Sanofi Pasteur.6 What was the efficacy, what were the shortcomings? Which additional data do we need for a dengue vaccine in travelers? The first trial to be completed was the CYD 23 trial.3 Conducted in five Asia-Pacific countries, this pivotal multicenter trial was a randomized controlled phase 3 trial conducted among more than 10,000 healthy children aged 2 to 14 years. The primary end point was defined as protective efficacy against symptomatic, virologically confirmed dengue (VCD) after the completion of three doses given 6 months apart. The incidence density of VCD during the 25 months’ surveillance was 1.8 (95% CI 1.5–2.1) in the vaccinees and 4.1 (95% CI 3.5–4.9) in the controls, translating into an overall protective efficacy of 56.5% (95% CI 43.8–66.4). The overall vaccine efficacy in the per-protocol analysis was similar in the intention-to-treat analysis. Efficacy was serotype specific (serotype 1: 50%, 95% CI 24.6–66.8; serotype 3: 78.4%, 95% CI 52.9–90.8; serotype 4: 75.3%, 95% CI 54.5–87.0). Of note was the lack of vaccine efficacy in DENV-naïve subjects (35.5%, and the 95% CI included 0: 95% CI
Corresponding Author: Professor Annelies Wilder-Smith, MD, PhD, Lee Kong Chian School of Medicine, Nanyang Technological University, Mandalay Road 11, Singapore 308533, Singapore. E-mail: [email protected]
−26.8 to 66.7). Vaccine efficacy was higher in older subjects. Results of the second trial were published in January 2015: the CYD 15 trial was conducted in Latin America with the same vaccine, the same trial design (randomized, observer-blind, and controlled study administering vaccine or placebo with three doses given 6 months apart), and the same duration of observation (25 months), with the only difference being the age group (9–16 years) and the larger sample size (20,875 children). Conducted in dengue-endemic areas of Brazil, Colombia, Mexico, Honduras, and Puerto Rico, the overall reduction of VCD in the vaccinated group versus unvaccinated group was 60.8% (CI 52%–68%). The serotype-specific efficacy was 50.3, 42.3, 74, and 77.7% for serotypes 1, 2, 3, and 4, respectively. In summary, the tetravalent chimeric live vaccine had a vaccine efficacy of 56.5% in Asia and 60.8% in Latin America. Both had serotype-dependent variation in the extent of efficacy, with protection against serotype 2 being the lowest. Both trials also showed that efficacy improved with prior flavivirus exposure and with age. The slightly better efficacy seen in the Latin American trial CYD 15 is most likely due to the fact that a higher age range was included. The improved efficacy in higher age groups in endemic populations can best be explained by the higher probability of having had flavivirus exposure in the past. This vaccine appears to boost and broaden preexisting flavivirus immunity rather than raising new protective immunity.5 Although efficacy was only moderate ranging between 56 and 61%, there is some good news: both trials showed impressive reductions in severe disease and hospitalization rates. In the Asian trial, the protection against dengue hemorrhagic fever (DHF) was 88.5%, and in Latin America, it was 95.5%.3,4 These clinically most important findings render this vaccine a promising vaccine. Protection against severe disease and death should be the main aim and, hence also, the main © 2015 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015
2
indication for a dengue vaccine in dengue-endemic countries. However, these impressive results showing protection against severe disease need to be interpreted with some guarded optimism. The observation period was only 25 months. This short observation period may provide insights only into what is also known from natural infection. Natural protection against dengue infection is observed as monotypic, heterotypic, and multitypic immunity.7 Heterotypic immunity is a short-lived immunity against all dengue serotype infections following a recent dengue infection. In other words, there is a short-lived protection (usually up to 6 months but also longer) in patients convalescing from a recent dengue infection if subsequently infected by another serotype infection. The shorter the interval, the greater the protection.8 A similar phenomenon was observed on a large scale in Cuba where the severity of dengue serotype 2 (DENV-2) disease in DENV-2 immune individuals increased as the interval between infections increased from 4 to 20 years.9 With shorter intervals, heterotypic immunity is protective; with longer intervals, it increases the severity of disease, a paradoxical challenge of dengue immunopathogenesis. A longer observation time is hence necessary to elucidate whether this high protection against severe disease will be sustained over time. Indeed, Sanofi Pasteur is conducting follow-up studies at all trial sites. The global enrollment of more than 30,000 children in the phases 2b and 3 studies has alleviated fears about the theoretical risk that dengue vaccination could predispose recipients to antibody-dependent enhancement and more severe disease.10 No enhanced disease was observed, at least for the observation period of 25 months in these two trials, and also not over a longer observation period from previous phases 1 and 2 trials.11 – 13 This is indeed reassuring. For the first time in the history of dengue vaccine development, we now have a safe and relatively efficacious vaccine at hand. Does this vaccine then open a realistic option for international travelers in the near future? Without doubt, the increasing trends and attack rates of dengue infections seen in travelers would justify the need for a dengue vaccine for travelers.2,14,15 Furthermore, vaccination of travelers may have the added benefit of reducing the risk of introduction of dengue to non-dengue-endemic countries via viremic returning travelers. However, there are several drawbacks of the Sanofi Pasteur vaccine that render this vaccine less viable in the travel medicine context. One, the trials have only included children to date. Two, the current schedule requires three doses given 6 months apart, which is not only inconvenient but practically impossible to implement in travelers who usually present to the travel medicine clinic within a relatively short time span before departure. Three, and this is perhaps the most important point, in immunologically naïve subjects, the efficacy was very low, only around 35.5% in the Asian trial J Travel Med 2015
Wilder-Smith
and 43.2% in the Latin American trial. This means that the majority of travelers will not be well protected given that they have not been exposed to dengue infections before. Such a low efficacy would not justify vaccinating travelers, would not be cost-effective, and would also lead to a low vaccine uptake by travelers. Although the vaccine-driven clinical protection against more severe disease may be higher, severe disease and death are very infrequent in travelers: the main concern in travelers (unlike the endemic population!), hence, is to reduce the incidence of dengue during travel. Dengue in travelers, although sometimes so serious that it leads to interruption of travel and evacuation, is usually transient and only rarely associated with severe complications.16,17 Having said this, however, this dengue vaccine may be justified in long-term expats or repeat travelers who are already flavivirus positive and hence will benefit more from this vaccine, and for whom the three-dose schedule may not be such an issue. The Sanofi Pasteur dengue vaccine is a major milestone in our fight against dengue. It is thought that Sanofi Pasteur will file for licensure in 2015. We would all have hoped for a higher efficacy, but in the absence of effective vector control measures and alternative vaccines, this vaccine is the best we have. Although this vaccine may play an important role in endemic countries in the years to come, its use in immunologically naïve international travelers is limited. But it may play a role in long-term expats or already dengue-exposed repeat travelers. Whether the many other dengue vaccine candidates now being developed will improve the efficacy will not be known for several years. Gaps in the knowledge of dengue immunology and pathogenesis, absence of a validated animal or human model of disease, and suboptimal assay platforms to measure immune responses following vaccination remain major hurdles to vaccine development, which still need to be overcome. References 1. Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol 2013; 5:299–309. 2. Wilder-Smith A, Deen JL. Dengue vaccines for travelers. Expert Rev Vaccines 2008; 7:569–578. 3. Capeding MR, Tran NH, Hadinegoro SR, 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 2014; 384:1358–1365. 4. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 372:113–123. 5. Wilder-Smith A. Dengue vaccines: dawning at last? Lancet 2014; 384:1327–1329. 6. Guy B, Saville M, Lang J. Development of Sanofi Pasteur tetravalent dengue vaccine. Hum Vaccin 2010; 6. 7. Halstead SB. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 2013; 31:4501–4507.
Dengue Vaccines for Travelers 8. Sabin AB. Research on dengue during World War II. Am J Trop Med Hyg 1952; 1:30–50. 9. Guzman MG, Kouri G, Valdes L, et al. Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks. Rev Panam Salud Publica 2002; 11:223–227. 10. Thomas SJ. Preventing dengue—is the possibility now a reality? N Engl J Med 2015; 372:172–173. 11. Leo YS, Wilder-Smith A, Archuleta S, et al. Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 y: phase II randomized controlled trial in Singapore. Hum Vaccin Immunother 2012; 8:1259–1271. 12. Sabchareon A, Lang J, Chanthavanich P, et al. Safety and immunogenicity of a three dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-year-old Thai children. Pediatr Infect Dis J 2004; 23:99–109.
3 13. Chanthavanich P, Luxemburger C, Sirivichayakul C, et al. Short report: immune response and occurrence of dengue infection in Thai children three to eight years after vaccination with live attenuated tetravalent dengue vaccine. Am J Trop Med Hyg 2006; 75:26–28. 14. Leder K, Torresi J, Brownstein JS, et al. Travel-associated illness trends and clusters, 2000–2010. Emerg Infect Dis 2013; 19:1049–1073. 15. Rocklov J, Lohr W, Hjertqvist M, Wilder-Smith A. Attack rates of dengue fever in Swedish travellers. Scand J Infect Dis 2014; 46:412–417. 16. Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353:924–932. 17. Wilder-Smith A, Tambyah PA. Severe dengue virus infection in travelers. J Infect Dis 2007; 195:1081–1083.
J Travel Med 2015
PERSPECTIVE
Dengue Vaccines for Travelers: Has the Time Come? Annelies Wilder-Smith, MD, PhD Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore DOI: 10.1111/jtm.12198
T
he need for a dengue vaccine is more pressing than ever, both for the endemic population and for international travelers.1,2 The recent completion of two efficacy trials for the live attenuated chimeric dengue vaccine in 20143,4 may signify the dawn of a new era in dengue control in dengue-endemic countries.5 Does it also signify a new era for dengue prevention in international travelers? To answer this question, it is important to first summarize the main findings from these two phase 3 trials evaluating a dengue vaccine that has to date gone furthest in development: the recombinant, live, attenuated, tetravalent vaccine developed by Sanofi Pasteur.6 What was the efficacy, what were the shortcomings? Which additional data do we need for a dengue vaccine in travelers? The first trial to be completed was the CYD 23 trial.3 Conducted in five Asia-Pacific countries, this pivotal multicenter trial was a randomized controlled phase 3 trial conducted among more than 10,000 healthy children aged 2 to 14 years. The primary end point was defined as protective efficacy against symptomatic, virologically confirmed dengue (VCD) after the completion of three doses given 6 months apart. The incidence density of VCD during the 25 months’ surveillance was 1.8 (95% CI 1.5–2.1) in the vaccinees and 4.1 (95% CI 3.5–4.9) in the controls, translating into an overall protective efficacy of 56.5% (95% CI 43.8–66.4). The overall vaccine efficacy in the per-protocol analysis was similar in the intention-to-treat analysis. Efficacy was serotype specific (serotype 1: 50%, 95% CI 24.6–66.8; serotype 3: 78.4%, 95% CI 52.9–90.8; serotype 4: 75.3%, 95% CI 54.5–87.0). Of note was the lack of vaccine efficacy in DENV-naïve subjects (35.5%, and the 95% CI included 0: 95% CI
Corresponding Author: Professor Annelies Wilder-Smith, MD, PhD, Lee Kong Chian School of Medicine, Nanyang Technological University, Mandalay Road 11, Singapore 308533, Singapore. E-mail: [email protected]
−26.8 to 66.7). Vaccine efficacy was higher in older subjects. Results of the second trial were published in January 2015: the CYD 15 trial was conducted in Latin America with the same vaccine, the same trial design (randomized, observer-blind, and controlled study administering vaccine or placebo with three doses given 6 months apart), and the same duration of observation (25 months), with the only difference being the age group (9–16 years) and the larger sample size (20,875 children). Conducted in dengue-endemic areas of Brazil, Colombia, Mexico, Honduras, and Puerto Rico, the overall reduction of VCD in the vaccinated group versus unvaccinated group was 60.8% (CI 52%–68%). The serotype-specific efficacy was 50.3, 42.3, 74, and 77.7% for serotypes 1, 2, 3, and 4, respectively. In summary, the tetravalent chimeric live vaccine had a vaccine efficacy of 56.5% in Asia and 60.8% in Latin America. Both had serotype-dependent variation in the extent of efficacy, with protection against serotype 2 being the lowest. Both trials also showed that efficacy improved with prior flavivirus exposure and with age. The slightly better efficacy seen in the Latin American trial CYD 15 is most likely due to the fact that a higher age range was included. The improved efficacy in higher age groups in endemic populations can best be explained by the higher probability of having had flavivirus exposure in the past. This vaccine appears to boost and broaden preexisting flavivirus immunity rather than raising new protective immunity.5 Although efficacy was only moderate ranging between 56 and 61%, there is some good news: both trials showed impressive reductions in severe disease and hospitalization rates. In the Asian trial, the protection against dengue hemorrhagic fever (DHF) was 88.5%, and in Latin America, it was 95.5%.3,4 These clinically most important findings render this vaccine a promising vaccine. Protection against severe disease and death should be the main aim and, hence also, the main © 2015 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015
2
indication for a dengue vaccine in dengue-endemic countries. However, these impressive results showing protection against severe disease need to be interpreted with some guarded optimism. The observation period was only 25 months. This short observation period may provide insights only into what is also known from natural infection. Natural protection against dengue infection is observed as monotypic, heterotypic, and multitypic immunity.7 Heterotypic immunity is a short-lived immunity against all dengue serotype infections following a recent dengue infection. In other words, there is a short-lived protection (usually up to 6 months but also longer) in patients convalescing from a recent dengue infection if subsequently infected by another serotype infection. The shorter the interval, the greater the protection.8 A similar phenomenon was observed on a large scale in Cuba where the severity of dengue serotype 2 (DENV-2) disease in DENV-2 immune individuals increased as the interval between infections increased from 4 to 20 years.9 With shorter intervals, heterotypic immunity is protective; with longer intervals, it increases the severity of disease, a paradoxical challenge of dengue immunopathogenesis. A longer observation time is hence necessary to elucidate whether this high protection against severe disease will be sustained over time. Indeed, Sanofi Pasteur is conducting follow-up studies at all trial sites. The global enrollment of more than 30,000 children in the phases 2b and 3 studies has alleviated fears about the theoretical risk that dengue vaccination could predispose recipients to antibody-dependent enhancement and more severe disease.10 No enhanced disease was observed, at least for the observation period of 25 months in these two trials, and also not over a longer observation period from previous phases 1 and 2 trials.11 – 13 This is indeed reassuring. For the first time in the history of dengue vaccine development, we now have a safe and relatively efficacious vaccine at hand. Does this vaccine then open a realistic option for international travelers in the near future? Without doubt, the increasing trends and attack rates of dengue infections seen in travelers would justify the need for a dengue vaccine for travelers.2,14,15 Furthermore, vaccination of travelers may have the added benefit of reducing the risk of introduction of dengue to non-dengue-endemic countries via viremic returning travelers. However, there are several drawbacks of the Sanofi Pasteur vaccine that render this vaccine less viable in the travel medicine context. One, the trials have only included children to date. Two, the current schedule requires three doses given 6 months apart, which is not only inconvenient but practically impossible to implement in travelers who usually present to the travel medicine clinic within a relatively short time span before departure. Three, and this is perhaps the most important point, in immunologically naïve subjects, the efficacy was very low, only around 35.5% in the Asian trial J Travel Med 2015
Wilder-Smith
and 43.2% in the Latin American trial. This means that the majority of travelers will not be well protected given that they have not been exposed to dengue infections before. Such a low efficacy would not justify vaccinating travelers, would not be cost-effective, and would also lead to a low vaccine uptake by travelers. Although the vaccine-driven clinical protection against more severe disease may be higher, severe disease and death are very infrequent in travelers: the main concern in travelers (unlike the endemic population!), hence, is to reduce the incidence of dengue during travel. Dengue in travelers, although sometimes so serious that it leads to interruption of travel and evacuation, is usually transient and only rarely associated with severe complications.16,17 Having said this, however, this dengue vaccine may be justified in long-term expats or repeat travelers who are already flavivirus positive and hence will benefit more from this vaccine, and for whom the three-dose schedule may not be such an issue. The Sanofi Pasteur dengue vaccine is a major milestone in our fight against dengue. It is thought that Sanofi Pasteur will file for licensure in 2015. We would all have hoped for a higher efficacy, but in the absence of effective vector control measures and alternative vaccines, this vaccine is the best we have. Although this vaccine may play an important role in endemic countries in the years to come, its use in immunologically naïve international travelers is limited. But it may play a role in long-term expats or already dengue-exposed repeat travelers. Whether the many other dengue vaccine candidates now being developed will improve the efficacy will not be known for several years. Gaps in the knowledge of dengue immunology and pathogenesis, absence of a validated animal or human model of disease, and suboptimal assay platforms to measure immune responses following vaccination remain major hurdles to vaccine development, which still need to be overcome. References 1. Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol 2013; 5:299–309. 2. Wilder-Smith A, Deen JL. Dengue vaccines for travelers. Expert Rev Vaccines 2008; 7:569–578. 3. Capeding MR, Tran NH, Hadinegoro SR, 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 2014; 384:1358–1365. 4. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 372:113–123. 5. Wilder-Smith A. Dengue vaccines: dawning at last? Lancet 2014; 384:1327–1329. 6. Guy B, Saville M, Lang J. Development of Sanofi Pasteur tetravalent dengue vaccine. Hum Vaccin 2010; 6. 7. Halstead SB. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 2013; 31:4501–4507.
Dengue Vaccines for Travelers 8. Sabin AB. Research on dengue during World War II. Am J Trop Med Hyg 1952; 1:30–50. 9. Guzman MG, Kouri G, Valdes L, et al. Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks. Rev Panam Salud Publica 2002; 11:223–227. 10. Thomas SJ. Preventing dengue—is the possibility now a reality? N Engl J Med 2015; 372:172–173. 11. Leo YS, Wilder-Smith A, Archuleta S, et al. Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 y: phase II randomized controlled trial in Singapore. Hum Vaccin Immunother 2012; 8:1259–1271. 12. Sabchareon A, Lang J, Chanthavanich P, et al. Safety and immunogenicity of a three dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-year-old Thai children. Pediatr Infect Dis J 2004; 23:99–109.
3 13. Chanthavanich P, Luxemburger C, Sirivichayakul C, et al. Short report: immune response and occurrence of dengue infection in Thai children three to eight years after vaccination with live attenuated tetravalent dengue vaccine. Am J Trop Med Hyg 2006; 75:26–28. 14. Leder K, Torresi J, Brownstein JS, et al. Travel-associated illness trends and clusters, 2000–2010. Emerg Infect Dis 2013; 19:1049–1073. 15. Rocklov J, Lohr W, Hjertqvist M, Wilder-Smith A. Attack rates of dengue fever in Swedish travellers. Scand J Infect Dis 2014; 46:412–417. 16. Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353:924–932. 17. Wilder-Smith A, Tambyah PA. Severe dengue virus infection in travelers. J Infect Dis 2007; 195:1081–1083.
J Travel Med 2015
