- Email: [email protected]
Dengue vaccine development: a 75% solution?
Comment
A completed clinical trial of vaccine efficacy should be cause for celebration for the billions of people who live in the 128 countries where dengue viruses (DENV) are transmitted.1,2 However, the celebration will be muted this time, as was the case after announcement of results of early clinical trials of vaccines for malaria and HIV.3,4 The low efficacies reported from trials of malaria and HIV vaccines were not entirely unexpected, since these pathogens are known for antigenic complexity and for their ability to successfully evade immune elimination. By contrast, each of the four DENV produces acute, self-limited infections that result in lifelong immunity. DENV are flaviviruses, members of a group of singlestranded RNA viruses that includes yellow fever and Japanese encephalitis viruses—highly effective liveattenuated vaccines have long been licensed for these two viruses that are safe and in extensive use.5,6 Over several decades, many live-attenuated dengue vaccine candidates have been derived by serial tissue culture passage, chimerisation, or the introduction of attenuating mutations.7 Phase 1 or 2 studies of these attenuated viruses, when tested individually, often generated excellent immunological responses leading to high optimism for vaccine efficacy. Thus, the overall efficacy of 30·2% (95% CI –13·4 to 56·6) in Arunee Sabchareon and colleagues’ clinical trial reported in The Lancet,1 of the live-attenuated tetravalent dengue-yellow fever 17D chimeric virus vaccine, comes as a complete surprise. Thai schoolchildren in Ratchaburi province were assigned to vaccine (n=2669) or control (n=1333), and one or more doses of vaccine reduced incidence of DENV3 and 4 febrile diseases by 80–90%, with a smaller reduction of cases due to DENV1. In view of this partial efficacy, might a single dose threecomponent dengue vaccine be used to combat dengue effectively? The occurrence of endemic severe dengue disease is known to require the circulation of multiple dengue serotypes. Available mathematical models might be used to test how a three-component dengue vaccine would be expected to behave if used strategically.8 In Sabchareon and colleagues’ trial,1 the incidence of mild disease caused by DENV2 was essentially identical in controls and in partially or fully vaccinated children. This result was particularly unexpected because the investigators had established in a pre-bled random www.thelancet.com Vol 380 November 3, 2012
sample that 91–92% of children receiving vaccine were flavivirus-immune owing to previous dengue virus infections or Japanese encephalitis vaccinations. In phase 2 trials of a tetravalent dengue vaccine, administration of vaccine to flavivirus-immune participants resulted in boosts in quantity and breadth of dengue neutralising antibody responses compared with immune responses in susceptible people.9 A broad neutralising antibody response was expected to protect against disease due to any DENV, as infection in dengueendemic countries of individuals with two or more different dengue viruses raises similar high titres of broadly cross-reactive neutralising antibodies and these antibodies serve as a correlate of sustained protection against severe disease.10 How can DENV2 breakthrough infections be explained? Sabchareon and colleagues1 speculate that the DENV2 genotype incorporated into the yellow fever chimera might not have raised protective antibodies against the different DENV2 genotype circulating in Thailand in 2009–11. An alternative explanation might be the failure to obtain balanced viraemias or immune responses when mixtures of the four DENV vaccines were given to susceptible human beings or rhesus monkeys.11 Dengue vaccine development, although increasingly based on new abilities to understand and manipulate viral genomes, remains an empirical process from the standpoint of efficacy and safety. Serious deficits remain in our understanding of the mechanism or mechanisms by which human beings are protected against initial and successive infections with the four DENV.12 Of interest, recent studies of human polyclonal antibodies raised after one DENV infection have localised the neutralisation function to IgG antibodies that attach to a quaternary virion structure along the lateral ridge of domain I and II.13 The interference process that I have described could have inhibited production of balanced primary serotype-specific immune responses to each of the four DENV and these type-specific antibodies might be needed to protect against dengue disease. This trial is a cautionary tale for investigators designing future dengue vaccine efficacy trials. A much larger group of vaccinees should have been studied serologically than was the case here. When flavivirus-immune populations are given complex dengue vaccines, the postvaccination
Science Photo Library
Dengue vaccine development: a 75% solution?
Published Online September 11, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61510-4 See Articles page 1559
1535
Comment
efficacy of DENV vaccines and the serological responses can only be interpreted in the context of prevaccination immune status. Of children receiving one or more vaccine doses, 32 dengue episodes among 5292 person-years of observation (0·6%) were admitted to hospital compared with 30 among 2630 person-years (1·1%) for controls, a 45·5% reduction. Parents everywhere will want to know if dengue vaccination will prevent fatal dengue shock syndrome. When charts were reviewed, only three children in the vaccinated group and two in the control group were judged to have had severe dengue; of these children, three were aged 10 years or older. Ample recent data from Thailand document the modal age of severe dengue leading to hospital admission to be in the vicinity of 11 years.14 Fortunately, Sanofi Pasteur has given tetravalent dengue vaccine to an additional 30 000 adults and children, mostly in dengue-endemic countries.1 Results from these ongoing vaccine trials should harden DENV-specific disease efficacy rates and provide direct evidence of vaccine efficacy for severe disease. Future dengue vaccine trials should provide robust evidence of efficacy against severe disease by selecting populations weighted to assure inclusion of sufficient numbers of atrisk children.
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Scott B Halstead 5824 Edson Lane, Bethesda, MD 20852, USA [email protected]
14
Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012; published online Sept 11. http://dx.doi.org/10.1016/S01406736(12)61428-7. Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 2012; 6: e1760. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004; 364: 1411–20. Francis DP, Heyward WL, Popovic V, et al. Candidate HIV/AIDS vaccines: lessons learned from the world’s first phase III efficacy trials. AIDS 2003; 17: 147–56. Monath TP, Cetron MS, Teuwen DE. Yellow fever vaccine. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines, 5th edn. Philadelphia: Saunders Elsevier, 2008: 959–1055. Halstead SB, Thomas SJ. Japanese encephalitis: new options for active immunization. Clin Infect Dis 2010; 50: 1155–64. Murphy BR, Whitehead SS. Immune response to dengue virus and prospects for a vaccine. Annu Rev Immunol 2011; 29: 587–619. Halloran ME, Longini IM, Struchiner CJ. Modes of action and time-varying VEs. In: The design and analysis of vaccine studies. New York: Springer, 2009: 131–52. Capeding RZ, Luna IA, Bomasang E, et al. Live-attenuated, tetravalent dengue vaccine in children, adolescents and adults in a dengue endemic country: randomized controlled phase I trial in the Philippines. Vaccine 2011; 29: 3863–72. Gibbons RV, Kalanarooj S, Jarman RG, et al. Analysis of repeat hospital admissions for dengue to estimate the frequency of third or fourth dengue infections resulting in admissions and dengue hemorrhagic fever, and serotype sequences. Am J Trop Med Hyg 2007; 77: 910–13. Guy B, Barban V, Mantel N, et al. Evaluation of interferences between dengue vaccine serotypes in a monkey model. Am J Trop Med Hyg 2009; 80: 302–11. Wahala WM, de Silva AM. The human antibody response to dengue virus infection. Viruses 2011; 3: 2374–95. de Alwis R, Smith SA, Olivarez NP, et al. Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci USA 2012; 109: 7439–44. Cummings DA, Iamsirithaworn S, Lessler JT, et al. The impact of the demographic transition on dengue in Thailand: insights from a statistical analysis and mathematical modeling. PLoS Med 2009; 6: e1000139.
I am a senior scientific adviser for the Dengue Vaccine Initiative (International Vaccine Institute, Seoul, South Korea). I declare that I have no conflicts of interest.
Self-harm behaviour: rethinking physical and mental health Published Online September 18, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61509-8 See Editorial page 1532 See Articles page 1568
1536
In The Lancet, Helen Bergen and colleagues1 present results derived from the Multicentre Study of Selfharm in England, which indicate that self-harm is associated with poor physical health as well as mental health. The findings are not novel,2 but the work adds to and reinforces several key points. In their cohort of 30 950 individuals who presented with self-harm at emergency departments in three regions of England between 2000 and 2007, mortality from both natural and external causes (eg, suicides, accidental poisoning, and accidents) was higher than in the general population for both male and female patients (standardised mortality ratio 3·6, 95% CI 3·5–3·8). The mean number of years
of life lost (YLL) for natural-cause deaths was 25·9 years (95% CI 25·7–26·0) for male patients and 25·5 years (25·2–25·8) for female patients. Mean YLL for externalcause deaths was 40·2 years (40·0–40·3) in male patients and 40·0 years (39·7–40·5) for female patients. Notably, natural-cause mortality was clearly linked to socioeconomic status (assessed by place of residence), increasing with economic deprivation (χ² trend for both sexes combined 51·0; p<0·0001). No such association was recorded for external-cause mortality (0·30; p=0·58). In addition to what might be expected for external causes such as suicide and accidental poisoning, diseases of the digestive and circulatory systems had www.thelancet.com Vol 380 November 3, 2012
A completed clinical trial of vaccine efficacy should be cause for celebration for the billions of people who live in the 128 countries where dengue viruses (DENV) are transmitted.1,2 However, the celebration will be muted this time, as was the case after announcement of results of early clinical trials of vaccines for malaria and HIV.3,4 The low efficacies reported from trials of malaria and HIV vaccines were not entirely unexpected, since these pathogens are known for antigenic complexity and for their ability to successfully evade immune elimination. By contrast, each of the four DENV produces acute, self-limited infections that result in lifelong immunity. DENV are flaviviruses, members of a group of singlestranded RNA viruses that includes yellow fever and Japanese encephalitis viruses—highly effective liveattenuated vaccines have long been licensed for these two viruses that are safe and in extensive use.5,6 Over several decades, many live-attenuated dengue vaccine candidates have been derived by serial tissue culture passage, chimerisation, or the introduction of attenuating mutations.7 Phase 1 or 2 studies of these attenuated viruses, when tested individually, often generated excellent immunological responses leading to high optimism for vaccine efficacy. Thus, the overall efficacy of 30·2% (95% CI –13·4 to 56·6) in Arunee Sabchareon and colleagues’ clinical trial reported in The Lancet,1 of the live-attenuated tetravalent dengue-yellow fever 17D chimeric virus vaccine, comes as a complete surprise. Thai schoolchildren in Ratchaburi province were assigned to vaccine (n=2669) or control (n=1333), and one or more doses of vaccine reduced incidence of DENV3 and 4 febrile diseases by 80–90%, with a smaller reduction of cases due to DENV1. In view of this partial efficacy, might a single dose threecomponent dengue vaccine be used to combat dengue effectively? The occurrence of endemic severe dengue disease is known to require the circulation of multiple dengue serotypes. Available mathematical models might be used to test how a three-component dengue vaccine would be expected to behave if used strategically.8 In Sabchareon and colleagues’ trial,1 the incidence of mild disease caused by DENV2 was essentially identical in controls and in partially or fully vaccinated children. This result was particularly unexpected because the investigators had established in a pre-bled random www.thelancet.com Vol 380 November 3, 2012
sample that 91–92% of children receiving vaccine were flavivirus-immune owing to previous dengue virus infections or Japanese encephalitis vaccinations. In phase 2 trials of a tetravalent dengue vaccine, administration of vaccine to flavivirus-immune participants resulted in boosts in quantity and breadth of dengue neutralising antibody responses compared with immune responses in susceptible people.9 A broad neutralising antibody response was expected to protect against disease due to any DENV, as infection in dengueendemic countries of individuals with two or more different dengue viruses raises similar high titres of broadly cross-reactive neutralising antibodies and these antibodies serve as a correlate of sustained protection against severe disease.10 How can DENV2 breakthrough infections be explained? Sabchareon and colleagues1 speculate that the DENV2 genotype incorporated into the yellow fever chimera might not have raised protective antibodies against the different DENV2 genotype circulating in Thailand in 2009–11. An alternative explanation might be the failure to obtain balanced viraemias or immune responses when mixtures of the four DENV vaccines were given to susceptible human beings or rhesus monkeys.11 Dengue vaccine development, although increasingly based on new abilities to understand and manipulate viral genomes, remains an empirical process from the standpoint of efficacy and safety. Serious deficits remain in our understanding of the mechanism or mechanisms by which human beings are protected against initial and successive infections with the four DENV.12 Of interest, recent studies of human polyclonal antibodies raised after one DENV infection have localised the neutralisation function to IgG antibodies that attach to a quaternary virion structure along the lateral ridge of domain I and II.13 The interference process that I have described could have inhibited production of balanced primary serotype-specific immune responses to each of the four DENV and these type-specific antibodies might be needed to protect against dengue disease. This trial is a cautionary tale for investigators designing future dengue vaccine efficacy trials. A much larger group of vaccinees should have been studied serologically than was the case here. When flavivirus-immune populations are given complex dengue vaccines, the postvaccination
Science Photo Library
Dengue vaccine development: a 75% solution?
Published Online September 11, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61510-4 See Articles page 1559
1535
Comment
efficacy of DENV vaccines and the serological responses can only be interpreted in the context of prevaccination immune status. Of children receiving one or more vaccine doses, 32 dengue episodes among 5292 person-years of observation (0·6%) were admitted to hospital compared with 30 among 2630 person-years (1·1%) for controls, a 45·5% reduction. Parents everywhere will want to know if dengue vaccination will prevent fatal dengue shock syndrome. When charts were reviewed, only three children in the vaccinated group and two in the control group were judged to have had severe dengue; of these children, three were aged 10 years or older. Ample recent data from Thailand document the modal age of severe dengue leading to hospital admission to be in the vicinity of 11 years.14 Fortunately, Sanofi Pasteur has given tetravalent dengue vaccine to an additional 30 000 adults and children, mostly in dengue-endemic countries.1 Results from these ongoing vaccine trials should harden DENV-specific disease efficacy rates and provide direct evidence of vaccine efficacy for severe disease. Future dengue vaccine trials should provide robust evidence of efficacy against severe disease by selecting populations weighted to assure inclusion of sufficient numbers of atrisk children.
1
2
3
4
5
6 7 8
9
10
11
12 13
Scott B Halstead 5824 Edson Lane, Bethesda, MD 20852, USA [email protected]
14
Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012; published online Sept 11. http://dx.doi.org/10.1016/S01406736(12)61428-7. Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 2012; 6: e1760. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004; 364: 1411–20. Francis DP, Heyward WL, Popovic V, et al. Candidate HIV/AIDS vaccines: lessons learned from the world’s first phase III efficacy trials. AIDS 2003; 17: 147–56. Monath TP, Cetron MS, Teuwen DE. Yellow fever vaccine. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines, 5th edn. Philadelphia: Saunders Elsevier, 2008: 959–1055. Halstead SB, Thomas SJ. Japanese encephalitis: new options for active immunization. Clin Infect Dis 2010; 50: 1155–64. Murphy BR, Whitehead SS. Immune response to dengue virus and prospects for a vaccine. Annu Rev Immunol 2011; 29: 587–619. Halloran ME, Longini IM, Struchiner CJ. Modes of action and time-varying VEs. In: The design and analysis of vaccine studies. New York: Springer, 2009: 131–52. Capeding RZ, Luna IA, Bomasang E, et al. Live-attenuated, tetravalent dengue vaccine in children, adolescents and adults in a dengue endemic country: randomized controlled phase I trial in the Philippines. Vaccine 2011; 29: 3863–72. Gibbons RV, Kalanarooj S, Jarman RG, et al. Analysis of repeat hospital admissions for dengue to estimate the frequency of third or fourth dengue infections resulting in admissions and dengue hemorrhagic fever, and serotype sequences. Am J Trop Med Hyg 2007; 77: 910–13. Guy B, Barban V, Mantel N, et al. Evaluation of interferences between dengue vaccine serotypes in a monkey model. Am J Trop Med Hyg 2009; 80: 302–11. Wahala WM, de Silva AM. The human antibody response to dengue virus infection. Viruses 2011; 3: 2374–95. de Alwis R, Smith SA, Olivarez NP, et al. Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci USA 2012; 109: 7439–44. Cummings DA, Iamsirithaworn S, Lessler JT, et al. The impact of the demographic transition on dengue in Thailand: insights from a statistical analysis and mathematical modeling. PLoS Med 2009; 6: e1000139.
I am a senior scientific adviser for the Dengue Vaccine Initiative (International Vaccine Institute, Seoul, South Korea). I declare that I have no conflicts of interest.
Self-harm behaviour: rethinking physical and mental health Published Online September 18, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61509-8 See Editorial page 1532 See Articles page 1568
1536
In The Lancet, Helen Bergen and colleagues1 present results derived from the Multicentre Study of Selfharm in England, which indicate that self-harm is associated with poor physical health as well as mental health. The findings are not novel,2 but the work adds to and reinforces several key points. In their cohort of 30 950 individuals who presented with self-harm at emergency departments in three regions of England between 2000 and 2007, mortality from both natural and external causes (eg, suicides, accidental poisoning, and accidents) was higher than in the general population for both male and female patients (standardised mortality ratio 3·6, 95% CI 3·5–3·8). The mean number of years
of life lost (YLL) for natural-cause deaths was 25·9 years (95% CI 25·7–26·0) for male patients and 25·5 years (25·2–25·8) for female patients. Mean YLL for externalcause deaths was 40·2 years (40·0–40·3) in male patients and 40·0 years (39·7–40·5) for female patients. Notably, natural-cause mortality was clearly linked to socioeconomic status (assessed by place of residence), increasing with economic deprivation (χ² trend for both sexes combined 51·0; p<0·0001). No such association was recorded for external-cause mortality (0·30; p=0·58). In addition to what might be expected for external causes such as suicide and accidental poisoning, diseases of the digestive and circulatory systems had www.thelancet.com Vol 380 November 3, 2012