Tetravalent Dengue Vaccine Reduces Symptomatic and Asymptomatic Dengue Virus Infections in Healthy Children and Adolescents Aged 2-16 Years in Asia and Latin America
Gustavo Olivera-Botello, Laurent Coudeville, Karen Fanouillere, Bruno Guy, Laurent Chambonneau, Fernando Noriega, Nicholas Jackson, CYD-TDV Vaccine Trial Group, José Luis Arredondo-García, Alain Bouckenooghe, Maria Rosario Capeding, Tawee Chotpitayasunondh, Mary Noreen Chua, Margarita Cortés Supelano, Carmen Deseda, Reynaldo Dietze, Carina Frago, Sri Rezeki S Hadinegoro, Chan Quang Luong, Hussain Imam Hj Muhammad Ismail, Revathy Nallusamy, Punnee Pitisuttithum, Humberto Reynales, Doris Maribel Rivera-Medina, Kusnandi Rusmil, Usa Thisyakorn, Ngoc Huu Tran, T Anh Wartel, Dewa Nyoman Wirawan, In-Kyu Yoon, Betzana Zambrano, Gustavo Olivera-Botello, Laurent Coudeville, Karen Fanouillere, Bruno Guy, Laurent Chambonneau, Fernando Noriega, Nicholas Jackson, CYD-TDV Vaccine Trial Group, José Luis Arredondo-García, Alain Bouckenooghe, Maria Rosario Capeding, Tawee Chotpitayasunondh, Mary Noreen Chua, Margarita Cortés Supelano, Carmen Deseda, Reynaldo Dietze, Carina Frago, Sri Rezeki S Hadinegoro, Chan Quang Luong, Hussain Imam Hj Muhammad Ismail, Revathy Nallusamy, Punnee Pitisuttithum, Humberto Reynales, Doris Maribel Rivera-Medina, Kusnandi Rusmil, Usa Thisyakorn, Ngoc Huu Tran, T Anh Wartel, Dewa Nyoman Wirawan, In-Kyu Yoon, Betzana Zambrano
Abstract
Background: Asymptomatic dengue virus-infected individuals are thought to play a major role in dengue virus transmission. The efficacy of the recently approved quadrivalent CYD-TDV dengue vaccine against asymptomatic dengue virus infection has not been previously assessed.
Methods: We pooled data for 3 736 individuals who received either CYD-TDV or placebo at 0, 6, and 12 months in the immunogenicity subsets of 2 phase 3 trials (clinical trials registration NCT01373281 and NCT01374516). We defined a seroconversion algorithm (ie, a ≥4-fold increase in the neutralizing antibody titer and a titer of ≥40 from month 13 to month 25) as a surrogate marker of asymptomatic infection in the vaccine and placebo groups.
Results: The algorithm detected seroconversion in 94% of individuals with a diagnosis of virologically confirmed dengue between months 13 and 25, validating its discriminatory power. Among those without virologically confirmed dengue (n = 3 669), 219 of 2 485 in the vaccine group and 157 of 1 184 in the placebo group seroconverted between months 13 and 25, giving a vaccine efficacy of 33.5% (95% confidence interval [CI], 17.9%-46.1%) against asymptomatic infection. Vaccine efficacy was marginally higher in subjects aged 9-16 years (38.6%; 95% CI, 22.1%-51.5%). The annual incidence of asymptomatic dengue virus infection in this age group was 14.8%, which was 4.4 times higher than the incidence for symptomatic dengue (3.4%).
Conclusions: The observed vaccine efficacy against asymptomatic dengue virus infections is expected to translate into reduced dengue virus transmission if sufficient individuals are vaccinated in dengue-endemic areas.
Keywords: Asia; Latin America; adolescents; asymptomatic dengue virus infection; children; dengue vaccine; symptomatic dengue virus infection.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.
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References
- Guzman MG, Harris E. Dengue. Lancet 2015; 385:453–65.
- 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; 384:1358–65.
- Hadinegoro SR, Arredondo-Garcia JL, Capeding MR et al. . Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 2015; 373:1195–206.
- 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; 372:113–23.
- Bhatt S, Gething PW, Brady OJ et al. . The global distribution and burden of dengue. Nature 2013; 496:504–7.
- Anders KL, Nga le H, Thuy NT et al. . Households as foci for dengue transmission in highly urban Vietnam. PLoS Negl Trop Dis 2015; 9:e0003528.
- Dussart P, Baril L, Petit L et al. . Clinical and virological study of dengue cases and the members of their households: the multinational DENFRAME Project. PLoS Negl Trop Dis 2012; 6:e1482.
- Yoon IK, Srikiatkhachorn A, Hermann L et al. . Characteristics of mild dengue virus infection in Thai children. Am J Trop Med Hyg 2013; 89:1081–7.
- Duong V, Lambrechts L, Paul RE et al. . Asymptomatic humans transmit dengue virus to mosquitoes. Proc Natl Acad Sci 2015; 112:14688–93.
- Fine P, Eames K, Heymann DL. “Herd immunity”: a rough guide. Clin Infect Dis 2011; 52:911–6.
- Kim TH, Johnstone J, Loeb M. Vaccine herd effect. Scand J Infect Dis 2011; 43:683–9.
- Rashid H, Khandaker G, Booy R. Vaccination and herd immunity: what more do we know? Curr Opin Infect Dis 2012; 25:243–9.
- Clark HF, Lawley D, Mallette LA, DiNubile MJ, Hodinka RL. Decline in cases of rotavirus gastroenteritis presenting to The Children's Hospital of Philadelphia after introduction of a pentavalent rotavirus vaccine. Clin Vaccine Immunol 2009; 16:382–6.
- Kaplan EH, Wein LM. Smallpox eradication in West and Central Africa: surveillance-containment or herd immunity? Epidemiology 2003; 14:90–2.
- Kwong JC, Pereira JA, Quach S et al. . Randomized evaluation of live attenuated vs. inactivated influenza vaccines in schools (RELATIVES) cluster randomized trial: Pilot results from a household surveillance study to assess direct and indirect protection from influenza vaccination. Vaccine 2015; 33:4910–5.
- Lapinleimu K, Stenvik M. Experiences with polio vaccination and herd immunity in Finland. Dev Biol Stand 1981; 47:241–6.
- Lee MS, Lee LL, Chen HY, Wu YC, Horng CB. Post mass-immunization measles outbreak in Taoyuan County, Taiwan: dynamics of transmission, vaccine effectiveness, and herd immunity. Int J Infect Dis 1998; 3:64–9.
- Myint TT, Madhava H, Balmer P et al. . The impact of 7-valent pneumococcal conjugate vaccine on invasive pneumococcal disease: a literature review. Adv Ther 2013; 30:127–51.
- Peltola H, Aavitsland P, Hansen KG, Jonsdottir KE, Nokleby H, Romanus V. Perspective: a five-country analysis of the impact of four different Haemophilus influenzae type b conjugates and vaccination strategies in Scandinavia. J Infect Dis 1999; 179:223–9.
- Piedra PA, Gaglani MJ, Kozinetz CA et al. . Trivalent live attenuated intranasal influenza vaccine administered during the 2003–2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children. Pediatrics 2007; 120:e553–64.
- Plans P. New preventive strategy to eliminate measles, mumps and rubella from Europe based on the serological assessment of herd immunity levels in the population. Eur J Clin Microbiol Infect Dis 2013; 32:961–6.
- Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med 2001; 344:889–96.
- Dagan R, Leventhal A, Anis E, Slater P, Ashur Y, Shouval D. Incidence of hepatitis A in Israel following universal immunization of toddlers. JAMA 2005; 294:202–10.
- Balmaseda A, Standish K, Mercado JC et al. . Trends in patterns of dengue transmission over 4 years in a pediatric cohort study in Nicaragua. J Infect Dis 2010; 201:5–14.
- Corbett KS, Katzelnick L, Tissera H, Amerasinghe A, de Silva AD, de Silva AM. Preexisting neutralizing antibody responses distinguish clinically inapparent and apparent dengue virus infections in a Sri Lankan pediatric cohort. J Infect Dis 2015; 211:590–9.
- Endy TP, Anderson KB, Nisalak A et al. . Determinants of inapparent and symptomatic dengue infection in a prospective study of primary school children in Kamphaeng Phet, Thailand. PLoS Negl Trop Dis 2011; 5:e975.
- Burke DS, Nisalak A, Johnson DE, Scott RM. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 1988; 38:172–80.
- Gordon A, Kuan G, Mercado JC et al. . The Nicaraguan pediatric dengue cohort study: incidence of inapparent and symptomatic dengue virus infections, 2004–2010. PLoS Negl Trop Dis 2013; 7:e2462.
- Timiryasova TM, Bonaparte MI, Luo P, Zedar R, Hu BT, Hildreth SW. Optimization and validation of a plaque reduction neutralization test for the detection of neutralizing antibodies to four serotypes of dengue virus used in support of dengue vaccine development. Am J Trop Med Hyg 2013; 88:962–70.
- Flipse J, Smit JM. The complexity of a dengue vaccine: a review of the human antibody response. PLoS Negl Trop Dis 2015; 9:e0003749.
- Salje H, Rodriguez-Barraquer I, Rainwater-Lovett K et al. . Variability in dengue titer estimates from plaque reduction neutralization tests poses a challenge to epidemiological studies and vaccine development. PLoS Negl Trop Dis 2014; 8:e2952.
- Crill WD, Hughes HR, Delorey MJ, Chang GJ. Humoral immune responses of dengue fever patients using epitope-specific serotype-2 virus-like particle antigens. PloS One 2009; 4:e4991.
- de Alwis R, Beltramello M, Messer WB et al. . In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. PLoS Negl Trop Dis 2011; 5:e1188.
- Katzelnick LC, Montoya M, Gresh L, Balmaseda A, Harris E. Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort. Proc Natl Acad Sci USA 2016; 113:728–33.
- Lai CY, Williams KL, Wu YC et al. . Analysis of cross-reactive antibodies recognizing the fusion loop of envelope protein and correlation with neutralizing antibody titers in Nicaraguan dengue cases. PLoS Negl Trop Dis 2013; 7:e2451.
- Matheus S, Pham TB, Labeau B et al. . Kinetics of dengue non-structural protein 1 antigen and IgM and IgA antibodies in capillary blood samples from confirmed dengue patients. Am J Trop Med Hyg 2014; 90:438–43.
- Tsai WY, Lai CY, Wu YC et al. . High-avidity and potently neutralizing cross-reactive human monoclonal antibodies derived from secondary dengue virus infection. J Virol 2013; 87:12562–75.
- Guy B, Jackson N. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nat Rev Microbiol 2016; 14:45–54.
- Martinez-Vega RA, Danis-Lozano R, Diaz-Quijano FA et al. . Peridomestic infection as a determining factor of dengue transmission. PLoS Negl Trop Dis 2015; 9:e0004296.
- Vikram K, Nagpal BN, Pande V et al. . An epidemiological study of dengue in Delhi, India. Acta Trop 2016; 153:21–7.
- Villar LA, Rojas DP, Besada-Lombana S, Sarti E. Epidemiological trends of dengue disease in Colombia (2000–2011): a systematic review. PLoS Negl Trop Dis 2015; 9:e0003499.
- Endy TP, Chunsuttiwat S, Nisalak A et al. . Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am J Epidemiol 2002; 156:40–51.
- Montoya M, Gresh L, Mercado JC et al. . Symptomatic versus inapparent outcome in repeat dengue virus infections is influenced by the time interval between infections and study year. PLoS Negl Trop Dis 2013; 7:e2357.
- Busch MP, Sabino EC, Brambilla D et al. . Duration of dengue viremia in blood donors and relationships between donor viremia, unfection incidence and clinical case reports during a large epidemic. J Infect Dis 2016; 214:49–54.
- Porter KR, Beckett CG, Kosasih H et al. . Epidemiology of dengue and dengue hemorrhagic fever in a cohort of adults living in Bandung, West Java, Indonesia. Am J Trop Med Hyg 2005; 72:60–6.
- Mammen MP, Pimgate C, Koenraadt CJ et al. . Spatial and temporal clustering of dengue virus transmission in Thai villages. PLoS Med 2008; 5:e205.
- Guy B, Nougarede N, Begue S et al. . Cell-mediated immunity induced by chimeric tetravalent dengue vaccine in naive or flavivirus-primed subjects. Vaccine 2008; 26:5712–21.
Source: PubMed