- Email: [email protected]
Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects
G Model
ARTICLE IN PRESS
JVAC-17610; No. of Pages 3
Vaccine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Commentary
Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects Kalichamy Alagarasu Dengue/Chikungunya Group, National Institute of Virology (Indian Council of Medical Research), 20A Dr Ambedkar Road, Pune 411001, Maharashtra, India
a r t i c l e
i n f o
Article history: Received 19 January 2016 Received in revised form 20 April 2016 Accepted 22 April 2016 Available online xxx Keywords: Dengue Dengvaxia Diagnosis IgM NS1 antigen ELISA
a b s t r a c t Diagnosis of dengue virus infections is complicated by preference for different diagnostic tests in different post onset days of illness and the presence of multiple serotypes leading to secondary and tertiary infections. The sensitivity of the most commonly employed diagnostic assays such as anti dengue IgM capture (MAC) ELISA and non structural protein (NS) 1 capture ELISA are lower in secondary and subsequent infections. Introduction of dengue vaccine in endemic regions will affect the way how dengue is diagnosed in vaccinated subjects. This viewpoint article discusses implications of introduction of dengue vaccine on the diagnosis of dengue infections in vaccinated subjects and the strategies that are needed to tackle the issue. © 2016 Elsevier Ltd. All rights reserved.
Dengue virus infection is one of the most common vector borne infection affecting tropical countries. The infection is caused by four serotypes of dengue virus and the clinical manifestation of the disease ranges from dengue fever, mild form of the disease, to severe forms of the disease, dengue hemorrhagic fever and dengue shock syndrome. Till now, there was no approved vaccine for dengue and recently a recombinant live attenuated tetravalent dengue vaccine (CYD-TDV) has been approved for use in Mexico, Philipines and Brazil. The approval of licensure of Dengvaxia, Sanofi Pasteur’s dengue vaccine by the Federal Commission for the Protection against Sanitary Risks (COFEPRIS), Mexico and Food and Drug Administration (FDA), Philippines and Brazil are considered as an important step for reduction of dengue disease burden by researchers involved in developing dengue vaccines and policy makers. At the same time, there are concerns that need to be resolved such as the duration of protection, price and overall impact of the vaccine on dengue transmission due to the lack of a vaccine for children below 9 years old [1]. However, the main issue that is ignored and needs immediate attention is the impact of introduction of dengvaxia on the strategies for diagnosis of dengue among vaccinated subjects. Diagnosis of dengue is complicated by the preference for different diagnostic tests at different post onset day (POD) of illness. Molecular tests detecting viral RNA are preferred during first 5 days of POD of illness, while the serological test detecting IgM antibodies
E-mail address: [email protected]
against the dengue virus (DENV) is preferred during later PODs of illness. Serological tests detecting presence of viral antigens, particularly non structural protein 1 (NS1) are used between 1and 8 POD of fever. Presence of four serotypes of DENV further complicates the issue and secondary infection with a heterologous serotype of DENV affects the sensitivity of serological tests that detects IgM antibodies and NS1 antigen. Secondary infections are characterized by higher levels of dengue-specific IgG antibodies that can cross react with other flaviviruses and lower or undetectable levels of IgM antibodies [2]. Reports indicate that the percentage of negative IgM results range from 5.5 to 35.0% in secondary dengue infections [3–6]. A report on four volunteers with primary, secondary and tertiary infections has shown that IgM response was not detectable even in the convalescent phase in two subjects during secondary infection and in three subjects during tertiary infection, respectively [7]. Thus, IgM response declines in successive infections. Despite these drawbacks, serological tests detecting IgM are the assays of choice in resource limited settings of dengue endemic countries and the diagnosis mostly based on single samples linked to clinical symptoms. NS1-based assays are tests of choice for patients reporting during the earlier POD of illness. The antibody response to dengue predominantly consists of antibodies toward envelope (E) protein of the virus. Hence, most of the serological assays employ the whole virus or envelope proteins as antigens. A recent study on two phase three trials of a recombinant live attenuated tetravalent dengue vaccine (CYD-TDV), which expresses only the E and prM proteins of the four serotypes of DENV
http://dx.doi.org/10.1016/j.vaccine.2016.04.070 0264-410X/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alagarasu K. Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.04.070
G Model JVAC-17610; No. of Pages 3 2
ARTICLE IN PRESS K. Alagarasu / Vaccine xxx (2016) xxx–xxx
Fig. 1. Hypothetical illustration of anti dengue IgM response in a vaccinated subject, if they acquire natural DENV infection after vaccination.
in a yellow fever Virus back bone, has reported that when administered in three doses at intervals of 6 months reduced overall dengue cases by 65%, hospitalization for dengue by 81% and severe dengue by 93% among children aged nine years or older. The vaccine efficacy was higher in subjects seropositive for dengue at the baseline compared to those who were seronegative for dengue at the baseline. In the trial conducted in the Latin American Countries, it was observed that the increase in the geometric mean titre (GMT) of neutralizing antibody after 28 days post second dose of vaccine was significantly higher in individuals seropositive at baseline as compared to those seronegative at baseline. However, the GMT of neutralizing antibody after 28 days post third dose were lower compared to the GMT after 28 days post second dose of vaccine in individuals seropositive at the baseline. A mild increase was observed in subjects seronegative at baseline. The vaccine efficacy reported in the trials was against virologically confirmed disease [1,8,9]. However, in a real scenario, dengue cases do not report to clinics at earlier POD of illness during which the virus can be detected by molecular tests. Details of how the dengue cases in the vaccinated group responded to antibody-based serological diagnosis, particularly IgM are not available from the trial. Since vaccine has been approved to be used in highly endemic regions where the seroprevalence of dengue is more than 60%, the number of dengue seropositive subjects receiving the vaccine will also be higher. If such individuals acquire infection after all scheduled (three) doses of vaccine, the natural infection will be mimicking pentarnary or multinary infection. The lower GMT of neutralizing antibody after 28 days of third dose compared to the GMT after 28 days post second dose of vaccine in individuals seropositive at the baseline in the phase III trial in Latin American countries also corroborates the suggestion that the antibody response becomes progressively weaker after secondary infections [9]. The question that whether these subjects will be positive for dengue-specific IgM remains unanswered. Since the IgM response is predominantly toward E and prM proteins and decreases with subsequent infections [3–7], in vaccinated subjects also, IgM response toward E and prM proteins might be still lower or undetectable (Fig. 1). In most of endemic regions, IgM-based assays is the first choice of diagnosis. Though NS1 antigen-based detection tests can be utilized, sensitivity of NS1-based tests decreases with POD of illness and in secondary infections [10]. Since the duration of fever and clinical symptoms were not different between vaccinated and unvaccinated subjects as observed in the efficacy surveillance phase and the long-term follow-up phase of the all the phase III trials of CYD-TDV [8], the chance of missing dengue diagnosis increases in vaccinated subjects who report to clinics on later time points (> 5 days). This might lead to a situation wherein the vaccine effectiveness will be overestimated in real world situations. It might also lead to a situation wherein there will be an over dependence on molecular tests, that are not feasible to be performed in primary health care
centres or NS1 antigen-based tests for which the sensitivity depends on the immune status (primary or secondary) and is not consistent across different days. Hence, there is an urgent need to develop new tools that can detect natural infections at later POD of illness among vaccinated subjects. Since the CYD-TDV expresses only the E and prM proteins of the four serotypes of DENV, assays that detect IgM antibodies to other proteins of the virus might be an attractive alternative to diagnose DENV infections in vaccinated subjects. Recently, NS1-based IgM capture ELISA and IgG capture ELISA have been developed and might find utility in differentiating antibodies elicited by CYD-TDV vaccine and natural dengue infection [11]. Detection of isotypes of antibodies against the virus that do not persist for a longer duration is another option. Anti IgA antibodies against dengue virus persist for shorter periods, and when used for diagnosis, detected dengue virus infections more accurately in secondary infections and at later POD of illness [12]. A recent study has reported that dengue viral RNA was detected at higher frequency in urine in POD of illness >7 days as compared to earlier POD of illness [13]. Hence, urine can serve as an alternative specimen for detection of viral RNA in subjects reporting at later POD of illness. However, the diagnostic accuracy of these assays cannot be evaluated unless it is tested against sera from vaccinated subjects who have contracted the disease after vaccination. Recently, a live attenuated tetravalent dengue vaccine TV003 consisting of viral proteins expressed in a dengue virus backbone, in a single dose, provided complete protection against dengue in a human challenge model [14]. It is possible that single dose vaccines may not affect the IgM response in progressive infections as compared to vaccines which need multiple doses. However, the results of the IgM assays in vaccinated individuals developing dengue, if any, need to be reported in the ongoing phase III trials of TV003. It is the responsibility of the vaccine developer to reveal the details of the IgM response in subjects who have acquired dengue after vaccination so that an awareness is created among the research community of endemic countries to look for suitable diagnostic alternatives that fits their country. This will lead to a real assessment of the vaccine effectiveness of CYD-TDV when introduced in different endemic countries in the coming years and also serve as a forerunner to other dengue vaccine development efforts. 1. Author’s contributions KA conceived the idea and prepared the manuscript 2. Source of Funding None 3. Declaration of interests None References [1] Statement by the Dengue Vaccine Initiative on Philippines Regulatory Approval of Sanofi Pasteur’s Dengue Vaccine, Dengvaxia®. Dengue vaccine initiative. (Accesed on December 28th at http://www.denguevaccines.org). [2] Rathakrishnan A, Sekaran SD. New development in the diagnosis of dengue infections. Expert Opin Med Diagn 2013;7:99–112. [3] Schilling SD, Ludolfs D, Van An L, Schmitz H. Laboratory diagnosis of primary and secondary dengue infection. J Clin Virol 2004;31:179–84. [4] Chanama S, Anantapreecha S, A-nuegoopipat A, Sa-gnasang A, Kurane L, Sawanpanyalert P. Analysis of specific IgM responses in secondary dengue virus infections: levels of positive rates in comparison with primary infections. J Clin Virol 2004;31:185–9. [5] Cordeiro MT, Silva AM, Britto AAC, Nascimento EJ, Magalhães MC, Guimarães GF, et al. Characterization of a dengue patient cohort in Recife, Brazil. Am J Trop Med Hyg 2007;77:1128–34.
Please cite this article in press as: Alagarasu K. Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.04.070
G Model JVAC-17610; No. of Pages 3
ARTICLE IN PRESS K. Alagarasu / Vaccine xxx (2016) xxx–xxx
[6] Domingo C, de Ory F, Sanz JC, Reyes N, Gascón J, Wichmann O, et al. Molecular and serologic markers of acute dengue infection in naive and flavivirusvaccinated travelers. Diagn Microbiol Infect Dis 2009;65:42–8. [7] Kosasih H, Yusuf H, Sudjana P, Alisjabhana B, Wuryadi S, Akterono, et al. Report of four volunteers with primary, secondary and tertiary dengue infections during a prospective cohort study. Dengue Bull 2006;30:87–92. [8] 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 2015;373(13):1195–206. [9] 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 2015;372:113–23. [10] Shan X, Wang X, Yuan Q, Zheng Y, Zhang H, Wu Y, et al. Evaluation of diagnostic accuracy of non structural protein 1 Ag based tests for dengue virus in Asian population: a meta-analysis. BMC Infect Dis 2015;15:360.
3
[11] Chao DY, Galula JU, Shen WF, Davis BS, Chang GJ. Nonstructural protein 1-specific immunoglobulin M and G antibody capture enzyme-linked immunosorbent assays in diagnosis of flaviviral infections in humans. J Clin Microbiol 2015;53:557–66. [12] Alagarasu K, Walimbe AM, Jadhav SM, Deoshatwar AR. A meta-analysis of the diagnostic accuracy of dengue virus specific IgA antibody based tests for detection of dengue infection. Epidemiol Infect 2016;144(4):876–86. [13] Van den Bossche D, Cnops L, Van Esbroeck M. Recovery of dengue virus from urine samples by real time RT-PCR. Eur J Clin Microbiol Infect Dis 2015;34(7):1361–7. [14] Kirkpatrick BD, Whitehead SS, Pierce KK, Tibery CM, Grier PL, Hynes NA, et al. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci Transl Med 2016;8(330): 330ra36.
Please cite this article in press as: Alagarasu K. Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.04.070
ARTICLE IN PRESS
JVAC-17610; No. of Pages 3
Vaccine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Commentary
Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects Kalichamy Alagarasu Dengue/Chikungunya Group, National Institute of Virology (Indian Council of Medical Research), 20A Dr Ambedkar Road, Pune 411001, Maharashtra, India
a r t i c l e
i n f o
Article history: Received 19 January 2016 Received in revised form 20 April 2016 Accepted 22 April 2016 Available online xxx Keywords: Dengue Dengvaxia Diagnosis IgM NS1 antigen ELISA
a b s t r a c t Diagnosis of dengue virus infections is complicated by preference for different diagnostic tests in different post onset days of illness and the presence of multiple serotypes leading to secondary and tertiary infections. The sensitivity of the most commonly employed diagnostic assays such as anti dengue IgM capture (MAC) ELISA and non structural protein (NS) 1 capture ELISA are lower in secondary and subsequent infections. Introduction of dengue vaccine in endemic regions will affect the way how dengue is diagnosed in vaccinated subjects. This viewpoint article discusses implications of introduction of dengue vaccine on the diagnosis of dengue infections in vaccinated subjects and the strategies that are needed to tackle the issue. © 2016 Elsevier Ltd. All rights reserved.
Dengue virus infection is one of the most common vector borne infection affecting tropical countries. The infection is caused by four serotypes of dengue virus and the clinical manifestation of the disease ranges from dengue fever, mild form of the disease, to severe forms of the disease, dengue hemorrhagic fever and dengue shock syndrome. Till now, there was no approved vaccine for dengue and recently a recombinant live attenuated tetravalent dengue vaccine (CYD-TDV) has been approved for use in Mexico, Philipines and Brazil. The approval of licensure of Dengvaxia, Sanofi Pasteur’s dengue vaccine by the Federal Commission for the Protection against Sanitary Risks (COFEPRIS), Mexico and Food and Drug Administration (FDA), Philippines and Brazil are considered as an important step for reduction of dengue disease burden by researchers involved in developing dengue vaccines and policy makers. At the same time, there are concerns that need to be resolved such as the duration of protection, price and overall impact of the vaccine on dengue transmission due to the lack of a vaccine for children below 9 years old [1]. However, the main issue that is ignored and needs immediate attention is the impact of introduction of dengvaxia on the strategies for diagnosis of dengue among vaccinated subjects. Diagnosis of dengue is complicated by the preference for different diagnostic tests at different post onset day (POD) of illness. Molecular tests detecting viral RNA are preferred during first 5 days of POD of illness, while the serological test detecting IgM antibodies
E-mail address: [email protected]
against the dengue virus (DENV) is preferred during later PODs of illness. Serological tests detecting presence of viral antigens, particularly non structural protein 1 (NS1) are used between 1and 8 POD of fever. Presence of four serotypes of DENV further complicates the issue and secondary infection with a heterologous serotype of DENV affects the sensitivity of serological tests that detects IgM antibodies and NS1 antigen. Secondary infections are characterized by higher levels of dengue-specific IgG antibodies that can cross react with other flaviviruses and lower or undetectable levels of IgM antibodies [2]. Reports indicate that the percentage of negative IgM results range from 5.5 to 35.0% in secondary dengue infections [3–6]. A report on four volunteers with primary, secondary and tertiary infections has shown that IgM response was not detectable even in the convalescent phase in two subjects during secondary infection and in three subjects during tertiary infection, respectively [7]. Thus, IgM response declines in successive infections. Despite these drawbacks, serological tests detecting IgM are the assays of choice in resource limited settings of dengue endemic countries and the diagnosis mostly based on single samples linked to clinical symptoms. NS1-based assays are tests of choice for patients reporting during the earlier POD of illness. The antibody response to dengue predominantly consists of antibodies toward envelope (E) protein of the virus. Hence, most of the serological assays employ the whole virus or envelope proteins as antigens. A recent study on two phase three trials of a recombinant live attenuated tetravalent dengue vaccine (CYD-TDV), which expresses only the E and prM proteins of the four serotypes of DENV
http://dx.doi.org/10.1016/j.vaccine.2016.04.070 0264-410X/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alagarasu K. Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.04.070
G Model JVAC-17610; No. of Pages 3 2
ARTICLE IN PRESS K. Alagarasu / Vaccine xxx (2016) xxx–xxx
Fig. 1. Hypothetical illustration of anti dengue IgM response in a vaccinated subject, if they acquire natural DENV infection after vaccination.
in a yellow fever Virus back bone, has reported that when administered in three doses at intervals of 6 months reduced overall dengue cases by 65%, hospitalization for dengue by 81% and severe dengue by 93% among children aged nine years or older. The vaccine efficacy was higher in subjects seropositive for dengue at the baseline compared to those who were seronegative for dengue at the baseline. In the trial conducted in the Latin American Countries, it was observed that the increase in the geometric mean titre (GMT) of neutralizing antibody after 28 days post second dose of vaccine was significantly higher in individuals seropositive at baseline as compared to those seronegative at baseline. However, the GMT of neutralizing antibody after 28 days post third dose were lower compared to the GMT after 28 days post second dose of vaccine in individuals seropositive at the baseline. A mild increase was observed in subjects seronegative at baseline. The vaccine efficacy reported in the trials was against virologically confirmed disease [1,8,9]. However, in a real scenario, dengue cases do not report to clinics at earlier POD of illness during which the virus can be detected by molecular tests. Details of how the dengue cases in the vaccinated group responded to antibody-based serological diagnosis, particularly IgM are not available from the trial. Since vaccine has been approved to be used in highly endemic regions where the seroprevalence of dengue is more than 60%, the number of dengue seropositive subjects receiving the vaccine will also be higher. If such individuals acquire infection after all scheduled (three) doses of vaccine, the natural infection will be mimicking pentarnary or multinary infection. The lower GMT of neutralizing antibody after 28 days of third dose compared to the GMT after 28 days post second dose of vaccine in individuals seropositive at the baseline in the phase III trial in Latin American countries also corroborates the suggestion that the antibody response becomes progressively weaker after secondary infections [9]. The question that whether these subjects will be positive for dengue-specific IgM remains unanswered. Since the IgM response is predominantly toward E and prM proteins and decreases with subsequent infections [3–7], in vaccinated subjects also, IgM response toward E and prM proteins might be still lower or undetectable (Fig. 1). In most of endemic regions, IgM-based assays is the first choice of diagnosis. Though NS1 antigen-based detection tests can be utilized, sensitivity of NS1-based tests decreases with POD of illness and in secondary infections [10]. Since the duration of fever and clinical symptoms were not different between vaccinated and unvaccinated subjects as observed in the efficacy surveillance phase and the long-term follow-up phase of the all the phase III trials of CYD-TDV [8], the chance of missing dengue diagnosis increases in vaccinated subjects who report to clinics on later time points (> 5 days). This might lead to a situation wherein the vaccine effectiveness will be overestimated in real world situations. It might also lead to a situation wherein there will be an over dependence on molecular tests, that are not feasible to be performed in primary health care
centres or NS1 antigen-based tests for which the sensitivity depends on the immune status (primary or secondary) and is not consistent across different days. Hence, there is an urgent need to develop new tools that can detect natural infections at later POD of illness among vaccinated subjects. Since the CYD-TDV expresses only the E and prM proteins of the four serotypes of DENV, assays that detect IgM antibodies to other proteins of the virus might be an attractive alternative to diagnose DENV infections in vaccinated subjects. Recently, NS1-based IgM capture ELISA and IgG capture ELISA have been developed and might find utility in differentiating antibodies elicited by CYD-TDV vaccine and natural dengue infection [11]. Detection of isotypes of antibodies against the virus that do not persist for a longer duration is another option. Anti IgA antibodies against dengue virus persist for shorter periods, and when used for diagnosis, detected dengue virus infections more accurately in secondary infections and at later POD of illness [12]. A recent study has reported that dengue viral RNA was detected at higher frequency in urine in POD of illness >7 days as compared to earlier POD of illness [13]. Hence, urine can serve as an alternative specimen for detection of viral RNA in subjects reporting at later POD of illness. However, the diagnostic accuracy of these assays cannot be evaluated unless it is tested against sera from vaccinated subjects who have contracted the disease after vaccination. Recently, a live attenuated tetravalent dengue vaccine TV003 consisting of viral proteins expressed in a dengue virus backbone, in a single dose, provided complete protection against dengue in a human challenge model [14]. It is possible that single dose vaccines may not affect the IgM response in progressive infections as compared to vaccines which need multiple doses. However, the results of the IgM assays in vaccinated individuals developing dengue, if any, need to be reported in the ongoing phase III trials of TV003. It is the responsibility of the vaccine developer to reveal the details of the IgM response in subjects who have acquired dengue after vaccination so that an awareness is created among the research community of endemic countries to look for suitable diagnostic alternatives that fits their country. This will lead to a real assessment of the vaccine effectiveness of CYD-TDV when introduced in different endemic countries in the coming years and also serve as a forerunner to other dengue vaccine development efforts. 1. Author’s contributions KA conceived the idea and prepared the manuscript 2. Source of Funding None 3. Declaration of interests None References [1] Statement by the Dengue Vaccine Initiative on Philippines Regulatory Approval of Sanofi Pasteur’s Dengue Vaccine, Dengvaxia®. Dengue vaccine initiative. (Accesed on December 28th at http://www.denguevaccines.org). [2] Rathakrishnan A, Sekaran SD. New development in the diagnosis of dengue infections. Expert Opin Med Diagn 2013;7:99–112. [3] Schilling SD, Ludolfs D, Van An L, Schmitz H. Laboratory diagnosis of primary and secondary dengue infection. J Clin Virol 2004;31:179–84. [4] Chanama S, Anantapreecha S, A-nuegoopipat A, Sa-gnasang A, Kurane L, Sawanpanyalert P. Analysis of specific IgM responses in secondary dengue virus infections: levels of positive rates in comparison with primary infections. J Clin Virol 2004;31:185–9. [5] Cordeiro MT, Silva AM, Britto AAC, Nascimento EJ, Magalhães MC, Guimarães GF, et al. Characterization of a dengue patient cohort in Recife, Brazil. Am J Trop Med Hyg 2007;77:1128–34.
Please cite this article in press as: Alagarasu K. Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.04.070
G Model JVAC-17610; No. of Pages 3
ARTICLE IN PRESS K. Alagarasu / Vaccine xxx (2016) xxx–xxx
[6] Domingo C, de Ory F, Sanz JC, Reyes N, Gascón J, Wichmann O, et al. Molecular and serologic markers of acute dengue infection in naive and flavivirusvaccinated travelers. Diagn Microbiol Infect Dis 2009;65:42–8. [7] Kosasih H, Yusuf H, Sudjana P, Alisjabhana B, Wuryadi S, Akterono, et al. Report of four volunteers with primary, secondary and tertiary dengue infections during a prospective cohort study. Dengue Bull 2006;30:87–92. [8] 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 2015;373(13):1195–206. [9] 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 2015;372:113–23. [10] Shan X, Wang X, Yuan Q, Zheng Y, Zhang H, Wu Y, et al. Evaluation of diagnostic accuracy of non structural protein 1 Ag based tests for dengue virus in Asian population: a meta-analysis. BMC Infect Dis 2015;15:360.
3
[11] Chao DY, Galula JU, Shen WF, Davis BS, Chang GJ. Nonstructural protein 1-specific immunoglobulin M and G antibody capture enzyme-linked immunosorbent assays in diagnosis of flaviviral infections in humans. J Clin Microbiol 2015;53:557–66. [12] Alagarasu K, Walimbe AM, Jadhav SM, Deoshatwar AR. A meta-analysis of the diagnostic accuracy of dengue virus specific IgA antibody based tests for detection of dengue infection. Epidemiol Infect 2016;144(4):876–86. [13] Van den Bossche D, Cnops L, Van Esbroeck M. Recovery of dengue virus from urine samples by real time RT-PCR. Eur J Clin Microbiol Infect Dis 2015;34(7):1361–7. [14] Kirkpatrick BD, Whitehead SS, Pierce KK, Tibery CM, Grier PL, Hynes NA, et al. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci Transl Med 2016;8(330): 330ra36.
Please cite this article in press as: Alagarasu K. Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.04.070