- Email: [email protected]
Bioethics of establishing a CHIM model for dengue vaccine development
International Journal of Infectious Diseases 84S (2019) S74–S79
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Bioethics of establishing a CHIM model for dengue vaccine development Anuradha Rose, Amrita Sekhar* Departments of Community Health, Bioethics, Christian Medical College, Vellore, Tamil Nadu, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 October 2018 Received in revised form 7 January 2019 Accepted 7 January 2019
Introduction: Controlled human infection models (CHIM) have been used in vaccine development to upselect and down-select potential vaccine candidates and to provide proof of vaccine efficacy, and have also been used as a basis for licensure of vaccines for cholera and typhoid by regulatory agencies. CHIM in dengue vaccines development: Dengue fever results in 400 million infections a year and is of significant health concern especially in India. There are currently no antivirals for the disease and the only licensed vaccine for dengue is not widely used owing to safety concerns. Controlled dengue human challenge models (DHCM) are currently being used to assess the efficacy of vaccines in development for dengue. Dengue CHIM in India: Conducting CHIM studies in India especially for evaluation of dengue vaccine candidates will be hugely beneficial as the disease is endemic to India and hence the effect of preexposure to the virus on vaccine safety and efficacy can be established. However, to date no CHIM studies have been conducted in India and there is a need to educate ethics committee members, policy makers and the public on the importance of such studies and what they entail. © 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Controlled human infection models Controlled dengue human challenge models Dengvaxia Dengue vaccine development
Introduction Dengue is a vector borne viral illness that results in 400 million infections a year. While most of these cases are asymptomatic, the burden of symptomatic dengue is estimated at 50–100 million infections per year (Stanaway et al., 2016). The disease spectrum in symptomatic dengue ranges from dengue fever which presents as self-limiting fever with rash, myalgia, arthralgia, thrombocytopenia and neutropenia to severe dengue resulting in vascular leak and shock. The development of vaccines and other therapeutics for dengue has been complicated owing to a multitude of factors including the lack of a known correlate of protection, complex and poorly understood disease pathogenesis resulting in various levels of disease severity, lack of a reliable animal model and the constantly changing viral landscape (Vannice et al., 2018). Several efforts have been made over the last few decades towards the development of dengue antivirals by targeting both structural and non-structural proteins of the dengue virus (DENV). Molecules targeting multifunctional enzymes NS3 and NS5, C
* Corresponding author at: Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, 632004, India. E-mail address: [email protected] (A. Sekhar).
protein, NS4B and those targeting viral entry have been explored (Low et al., 2017). Many drugs such as chloroquine, prednisolone, balapiravir etc. have been repurposed by researchers for dengue. However, though these drugs have been found to be safe, so for none of them have been effective for combating dengue (Low et al., 2014; Nguyen et al., 2013). Vector control efforts for dengue are centred around interventions that minimize oviposition sites of mosquitoes, insecticides which are applied on a rotation basis to prevent the emergence of resistance in the mosquito population, genetically modified mosquitoes which are sterile (Winskill et al., 2015) and the use of Wolbachia. Wolbachia, a bacterium, infects ovaries and testes of the Aedes mosquito and is able to alter host reproduction, thereby affecting the vector breeding cycle (Hoffmann et al., 2011; Nguyen et al., 2015). It also blocks the replication of the dengue virus (DENV) in the salivary gland of the mosquito. There are many ongoing efforts towards the development of dengue vaccines using different platforms technologies. So far the only vaccine for dengue; ‘Dengvaxia’ developed by Sanofi Pasteur was licensed in 2015 (Guy et al., 2015). This vaccine has been licensed by WHO and approved for use by the regulatory authorities in 20 countries in areas endemic for dengue for the age group 9–45 years. The other more advanced vaccine candidates which are in various stages of clinical trials include (Torresi et al., 2017); (a) TV003/TV005- developed by NIAID and the Butantan
https://doi.org/10.1016/j.ijid.2019.01.013 1201-9712/© 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
S75
Institute, (b) TDV- developed by Inviragen and Takeda, (c) TDENdeveloped by GSK and the Walter Reed Institute, (d) V180 developed by Merck and Hawaii Biotech and (e) DIME 100 developed by the US Naval Medical institute. Current efforts to manage the disease revolve around supportive care with an emphasis on close clinical monitoring especially during the critical phase of the illness and vector control to prevent disease spread.
subsided. For CHIM studies involving agents with known treatments, all volunteers whether they develop symptoms of infection or not are administered treatment after a pre-defined time-period. After this pre-defined period, volunteers are administered treatment whether they show signs of the infection or not.
Dengvaxia vaccine
Vaccine development for dengue has been extremely challenging for a multitude of reasons including the lack of a known correlate of protection and the lack of a correlation between clinical outcomes and the level of neutralizing antibodies. Controlled dengue human challenge models (DHCMs) can serve as a useful tool to up-select or down-select potential vaccine candidates before undertaking large scale clinical trials in dengue endemic regions. In addition, in the absence of a reliable animal model, a DHCM could also help in identifying a correlate of protection and expand our current understanding of the disease (Vannice et al., 2018). An ideal DHCM should have objective and reproducible endpoints and these end points should be reached without causing significant illness in volunteers Dengue human infection models have been used since the 1900s and have contributed to several insights on the disease including establishing it as a viral disease, defining the periods of incubation and infectivity of the virus in humans and mosquitoes, transmission patterns, clinical symptoms and features, homotypic immunity, cross protection, etc. (Cassetti and Thomas, 2014) There are currently two different DHCMs which are being used to evaluate vaccine efficacy. The first model (an infection model) uses a modified strain of the DENV-2 as a challenge strain (DEN2 D 30) and has been developed by NIH. When administered in challenge studies, this strain induces viremia in all volunteers, rash in 80% of the volunteers and neutropenia in 27% of the volunteers. Therefore, the primary end point used in this model to assess vaccine efficiency is viremia. The model induces mild clinical signs/ symptoms of dengue and lower levels of viremia which are highly reproducible. Additionally, as volunteers develop only mild symptoms of dengue (infection model) this model can be studied in an outpatient setting (Larsen et al., 2015). The second model developed by the Walter Reed Army Institute of Research (WRAIR) is a disease model. Initially, 7 strains of DENV of all four serotypes were tested in challenges studies and only DENV-1 and DENV-3 challenge strains were found to be suitable for use as defined by the clinical endpoint of dengue fever in infected individuals who were dengue naïve at the time of challenge (Larsen et al., 2015; Lyons, 2014). In this model, the subjects are monitored closely either in an inpatient/hotel setting for a period of 14 days post-challenge. The clinical end point is dengue fever which is defined as sustained fever (oral temperature >38 C for 48 h) accompanied by viremia (detectable by culture) with two or more of the following symptoms; headache, myalgia, erythematous rash, retro-orbital pain or arthralgia (Mammen et al., 2014). These two models have been subsequently used to evaluate vaccine efficacy of dengue vaccine candidates. In both models, the virus is administered parenterally, and the treatment involves the medical management of the symptoms The NIH model has been used to evaluate the efficacy of the TV003 vaccine candidate which is a live attenuated tetravalent vaccine particularly in those individuals who are seronegative to dengue prior to vaccination (Kirkpatrick et al., 2016). The study revealed that TV003 afforded complete protection after challenge with DEN2 D 30 administered 6 months after vaccination in dengue naïve volunteers. The Walter Reed model has been tested in volunteers who have been previously vaccinated with the tetravalent vaccine (Mammen
Dengvaxia CYD-TDV is a live-attenuated tetravalent vaccine which contains four recombinant live-attenuated chimeric viral vaccines on the yellow fever vaccine backbone. CYD-TDV was found to be safe and immunogenic in efficacy trials carried out in Asia and Latin America (Capeding et al., 2014; Villar et al., 2015). However, data from studies to assess the long-term safety of the vaccine revealed that three years post vaccination, the risk of hospitalization with dengue was higher in vaccine recipients as compared to controls and this risk was especially enhanced in children <9 years of age (Hadinegoro et al., 2015). Sanofi has since then conducted additional studies to ascertain the risk of the vaccine (Sridhar et al., 2018). The findings of their studies suggest that the vaccine behaves differently in individuals that are seropositive for dengue as compared to those that are seronegative for dengue at the time of vaccination, with seronegative individuals mounting varying levels of immune responses to the four serotypes. In seronegative individuals, the vaccine efficacy is lower, and they have an increased risk of hospitalized dengue and severe dengue from year 3 (after vaccination). The most probable explanation for this observation is antibody dependent enhancement with the vaccine mimicking the primary infection in seronegative individuals (Katzelnick et al., 2017). In the light of these findings WHO now recommends that countries considering Dengvaxia vaccination should have a prescreening strategy in which only dengue seropositive individuals are vaccinated (WER, 2018; Wilder-Smith et al., 2019). Controlled human infection models (CHIM) in vaccine development CHIM studies involve the intentional infection of a consenting healthy human volunteer with a virulent organism under controlled conditions. In a CHIM study, a well-characterized, attenuated and epidemiologically relevant strain of an infectious agent is administered in a controlled dose by a specific route to carefully selected and consenting healthy adult volunteers. The natural history of the infection, virulence, persistence in the body and the possibility of secondary infection are well established before the challenge strain is administered. In addition, the challenge strain is manufactured under Good Manufacturing Practice conditions. CHIM studies require skilled scientists, safe microbiology, excellent clinical facilities, and careful recruitment, monitoring and governance. CHIM studies in vaccine development are used to up-select or down-select potential vaccine candidates, test vaccine efficacy, reduce costs and accelerate the development of vaccines. In a CHIM study to test vaccines, volunteers are administered the vaccine and then infected with the infectious agent that they have been vaccinated against after a defined time period. They are then carefully monitored by trained health professionals and scientists, usually for a period of 10 to 14 days post infection for signs of viremia, infection etc. In all CHIM studies volunteers are followed up carefully until all detectable signs of infection (viremia/parasitemia etc.) have
Controlled human infection models in dengue and dengue vaccine development
S76
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
et al., 2014; Sun et al., 2013). In the challenge experiments, volunteers who had been previously vaccinated (between 8–42 months prior to challenge) were challenged with either DENV-1 or DENV-3 challenge strains. The study revealed that while all volunteers were immune to challenge through DENV-1 some volunteers developed dengue fever when challenged with DENV-3. This study further affirms the need to have long-term safety and follow up studies following large scale field efficacy trials. While both these models serve as useful tools to evaluate vaccine efficacy, they have their limitations. Since the NIH model is a model of infection and not disease it may not be well suited to provide information on severe forms of dengue pathogenesis and cannot be used to test therapeutics designed to address severe dengue. The Walter Reed model causes dengue fever and therefore requires it to be carried out in an in-patient setting with careful monitoring and clinical management. It has the potential to provide an understanding of more severe forms of dengue as well as help to evaluate therapeutics that modify the course of the illness. However, it may need more volunteers depending on how many actually meet the clinical end point of dengue disease when administered the challenge agent. So far, in both these models, challenge strains (based on failed vaccine candidates) have been developed for only a few serotypes; DENV-1 and DENV-3 in the Walter Reed model and DENV-2 in the NIH model. Another drawback of both these models is that since the virus is administered parenterally, the way the disease is induced differs from natural infection in terms of incubation period and the development of both innate and adaptive immunity. Despite these limitations, these models serve as extremely valuable tools to vaccine manufacturers in minimizing the risk of dengue vaccine development. The vaccine efficacy as determined by the dengue CHIMs still needs to be compared to that determined in classical Phase III trials. DHCMs can help supplement classical phase III studies for tetravalent dengue vaccines especially when efficacy cannot be demonstrated to all four serotypes due to a lack of naturally circulating strains to all serotypes. Conducting CHIM studies in India There are several advantages and reasons that support conducting CHIM studies in India. However, they require a consideration of several factors that need additional focus and monitoring as compared to more developed countries.
Building Indian research capacity: CHIM studies require rigorous research protocols and researcher sensitivity when dealing with volunteers. Both researchers and ethics committees (ECs) that review, permit and monitor these studies will need training. CHIM studies therefore provide an opportunity for India to ‘build local research capacities, clinical facilities, laboratory diagnostics, experimental medicine, clinical governance and regulatory confidence (Gordon et al., 2017). Scientific advancement for public benefit: CHIM studies can help accelerate drug and vaccine development and efficacy testing for diseases that are relevant to the national interest. Animal studies are sometimes inadequate in predicting human responses to interventions. The assessment of preliminary drug or vaccine efficacy could show that a candidate is likely to be ineffective thereby preventing unnecessary exposure of thousands of people in large Phase III trials. While for many diseases, it is unlikely that CHIM studies will replace Phase III trials, they would help in licensing a product followed by strict post marketing surveillance. CHIM studies have played a key role in development of vaccines against enteric diseases including the cholera vaccine Dukoral and typhoid vaccine Ty21a (Gordon et al., 2017). Risks and benefits in CHIM studies: CHIM studies carry different risk than other studies because the harm caused in them is intentional (Balasingam et al., 2014). However, the mere prospect of risk does not make a study unethical. In all types of studies, scientists plan for risks in order to protect participants and the community before they conduct the (Bambery et al., 2016) study. CHIM studies generally involve low risks because microbes used in the study are well characterized and the infection caused by the study can easily be managed. Furthermore, these studies include carefully considered and planned risk-mitigation strategies, monitoring and oversight that safeguard volunteer safety. Some argue that the risks undertaken by CHIM study volunteers is not more than that undertaken by volunteer firefighters or kidney donors. The benefits of conducting the study need to outweigh the risk to volunteers. In the absence of CHIM studies, more people are at risk of exposure to ineffective vaccines that can potentially cause harm in Phase III trials (Bambery et al., 2016). ECs in India need to be trained and sensitized to the risks posed by CHIM studies.
Ethics of CHIM studies
Infrastructure requirements
Local relevance: Currently, most CHIM studies are conducted in non-endemic countries where volunteers are typically college students from high-income countries who do not have the same genetic profile and pre-exposure environmental factors as an Indian resident. Therefore, conducting CHIM studies in India in a disease endemic setting makes the research more relevant to the local population. It allows for a better understanding of the effect of genetics, pre-exposure, immune status and environmental factors that may play a part in disease manifestation. Locally significant disease information could make drug or vaccine development more likely to succeed in the populations that need such interventions the most. The potential social and scientific benefits of indigenously developed drugs or vaccines to tackle diseases of public health importance in India is immense and there is a moral and public health necessity for locally conducted, locally relevant research. Development of vaccines and CHIM models for diseases not endemic to western countries by scientists in western countries may pose ethical problems, as the volunteers will be drawn from a population that will not benefit from the vaccine being developed.
Infrastructure and clinical facilities: The conduct of CHM requires the development of excellent infrastructure and clinical facilities. In India we currently may not be equipped to monitor adverse events during and after a CHIM study in any but a few clinical care settings. One proposal is to only allow renowned academic institutions to conduct CHIM studies so that issues of trust, control and scientific rigour involved in complex study designs are well balanced to protect the research participants. These facilities would need to be certified according to specific guidelines before the study can take place, and closely monitored. This is particularly important as study protocols for conducting established CHIM studies in India are likely to be very different than western countries. For example, in the UK, a typhoid challenge study is conducted in an out-patient setting where the volunteer returns home but has daily visits to the study centre for tests. However, in India given the varied and often inadequate sanitation infrastructure and hygiene practices, there might be a need to quarantine volunteers for the duration of the study to contain the pathogen and ensure that it does not spread to the community.
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
Challenge strain production: Infrastructure requirements also relate to the production of challenge strains. This would not be feasible without the proper facilities to assure quality, Good Manufacturing Practice (GMP) certifications, and a regulated delivery pathway to the volunteer.
Protection of volunteers and public engagement Fair selection: The strictest care should be taken to avoid exploitation, particularly of vulnerable members of society. While poverty and education should not be used to discriminate against those who desire to participate, in India, till clear protocols are made and the consent procedures are developed, only healthy, educated adults who are empowered to protect themselves should be included in a CHIM study. Informed consent: Special attention should be paid to creation of consent documents and procedures so that volunteers clearly understand what their participation entails. Volunteers and their families will require long and secure counselling before, during and after the study by a sensitive and well-trained multidisciplinary team. Research teams may need to continually assess volunteer consent after enrolling them in the study, recognizing that a volunteer has the right to discontinue participation at any time. Compensation: Participants will need to be compensated for their time spent in the study, which may cause loss of their regular wages and travel expense to the study site. In addition, if participants are in an in-patient facility, they should be compensated for the time away from their homes and families. Standard ways of compensating volunteers should be defined prior to starting the studies. In addition to this, as with all clinical research, compensation should be given in the event of adverse events. Care should be taken to design methods to ensure that the compensation does not cloud the decision of the participant to participate in the study. In a CHIM study conducted in Kenya, volunteers were offered financial compensation for transportation and time away from potential income generation opportunities or actual work. Participants were offered the idea of compensation, but the amounts were not disclosed till after the participants were enrolled in the study (Hodgson et al., 2015). Motivation for participation: Research has shown that participants are motivated by a variety of factors to participate in research involving risks (Stunkel and Grady, 2011) Therefore, efforts should be made to understand the motivations of the volunteer to participate in the study. The inclusion and exclusion criteria should include psychological preparedness of volunteers and their families. Public engagement: Researchers have highlighted the importance of understanding community perceptions of risk, disease severity, treatment availability and effectiveness of vaccines to prevent disease before designing CHIM studies (Gordon et al., 2017; Hodgson et al., 2015). Locally tailored consultation with and education of the public is essential to addressing anxieties that CHIM studies in the Indian context are likely to generate. Lessons from the experience of researchers in Kenya revealed that four years of stakeholder consultations greatly increased the understanding and acceptance of CHIM studies in their communities.
Regulations and governance The WHO Expert Committee on Biological Standardization, 2016 report titled, ‘Human Challenge Trials for Vaccine Development: regulatory considerations’, recognized that the regulation of
S77
CHIM trials need to be well defined by the national regulatory authorities and vaccine developers. In the US a CHIM study is subject to FDA regulations but in the EU, CHIM studies require Institutional Review Board approvals but not regulatory approvals (Balasingam et al., 2014). There are no comparable regulations in India as till date no CHIM study has been done in the country There is a need to develop a roadmap/guidance for conduct, review and monitoring of CHIM studies in India which should be endorsed by both the Indian Council for Medical Research (ICMR) and the Central Drugs Standards Control Organization (CDSCO), the national regulatory authority in the country before CHIM studies can be initiated in the country. At least initially it is very likely that CHIM studies in India will involve the import of challenge strains and therefore regulatory requirements and permissions for strain import will need to be carefully considered. Special ethical issues with DHCM studies As with all CHIM studies, the DHCM requires a careful consideration of risk-benefit, study design with respect to inclusion-exclusion criteria and carefully designed end points, challenge strain, informed consent, clinical facilities, and ethical, legal and regulatory requirements (Darton et al., 2015). However, the following points need to be carefully considered for a DHCM. Scientific validity In general, a dengue infection with a particular serotype of the virus results in the generation of homotypic serotype specific antibodies as well as heterotypic protective immunity from that serotype to other serotypes which is short lived (1.6 years) (Anderson et al., 2014). Therefore, the timing of challenge studies to evaluate vaccine efficacy is very important. If the challenge study is conducted soon after vaccination and within the window of heterotypic protective immunity, then it has the potential to provide misleading results especially on inferences made on the long-term heterotypic protection afforded by the vaccine (Vannice et al., 2018). The clinical end points need to be carefully defined in DHCMs in order for them to provide crucial information on the efficacy of therapeutics. For example, a clinical end point of viremia works well for the NIH model but for the WRAIR model dengue fever is a better end point. Social value The acceleration of production of an efficient vaccine will be of immense social value for a dengue endemic country with high mortality and morbidity rates. The previous studies and lessons learnt make it imminently possible to develop a good vaccine in a reasonable time frame using the DHCM. However, this should never be at the expense of participant safety and harm to participants. This is especially relevant in the light of the information provided by the studies on CYD-TDV. Risks Lessons learned from the studies on CYD-TDV have indicated that in the absence of previous dengue exposure the tetravalent vaccine partially mimics primary infection and therefore predisposes the vaccinated dengue naïve individuals to a greater risk of severe dengue on subsequent infection due to the presence of broadly cross reactive non-neutralizing antibodies (Sridhar et al., 2018). This is an important finding that needs to be kept in mind while designing DHCM studies. In the DHCM study of previously vaccinated volunteers with DENV-1 and DENV- 3 challenge strains,
S78
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
the volunteers were first screened for the presence of neutralizing antibodies for the two serotypes to qualify for the challenge experiments (Sun et al., 2013). Establishing the sero-status of the volunteers through strict and rigorous inclusion and exclusion criteria is therefore crucial in dengue challenge studies. This is especially true in in dengue endemic countries where most people have had prior exposure to the disease. Dengue endemic countries should use the NIH model (infection model) in DHCM studies in order to ensure volunteer safety. This is especially important as there is no known treatment for the disease. All volunteers need to be followed up carefully after the study and any intervention tested and found to be beneficial should be administered to them.
Acknowledgements The authors would like to thank and acknowledge Ms. Gayatri Ganesh for her valuable contributions to this paper. Funding This article is part of a supplement entitled ‘Dengue Fever in India’ which is sponsored by the Department of Biotechnology, Government of India, and collated by the Translational Health Science and Technology Institute. Conflict of interest
Public opinion Outbreaks of dengue and media reports on mortality and poor responses from the medical sector has created a certain level of fear of the disease. Adequate community engagement and discussions with the public are essential to prevent public backlash against volunteers or health personnel involved in DHCM studies. This is especially important as there is no known treatment for the disease. Public harm The studies carried out thus far using DHCMs have been in areas which are non-endemic for dengue and therefore there is little risk for secondary transmission of dengue viruses in the community. However, if such studies are to be replicated in India and other endemic countries, they will have to be carried out under carefully controlled in-patient settings. Within these settings it is pertinent to ensure proper treatment and containment of patient samples and waste materials as well as deployment of appropriate mosquito control measures to safeguard against secondary transmission. This is especially important in India where access to general health care is not uniform across geographic locations and social strata. Participants should be followed up regularly for adequate periods of time. Plans for long term safety and surveillance should be carefully made. Any intervention which has been found to be effective should be provided to all volunteers after the study period. Conclusions DHCM studies have great advantages in terms of fast tracking a good vaccine for a disease which causes significant morbidity and mortality in endemic countries. The strains developed by NIH and WRAIR for dengue challenge studies have their inherent limitations. While significant care has been taken in these studies to minimize harm to the volunteers, future DHCM studies need to be designed very carefully especially in the light of the safety data from the CYD-TDV vaccine. Participant safety needs to remain at the forefront of such studies. In addition, while DHCMs offer many valuable insights into dengue and provide for the up-selection and down-selection of potential therapeutic targets including vaccines they are unlikely to serve as a replacement for a classical Phase III trial at least till the efficacy for a vaccine from both a DHCM and a Phase III trial can be compared. Meanwhile it is essential to invest in infrastructure development, and the training or researchers, ethics committee members and regulators in the ethics of CHIM and DHCM studies in order to be able to plan these studies in India in the future. Prior to planning DHCM studies, India should build expertise and experience in planning, conduct and supervision of CHIM studies by undertaking such studies on infectious diseases such as typhoid that are endemic to India and have wellestablished CHIM models with well-known treatments.
The authors declare no conflict of interest and no funding or ethics approval was sought for writing this review. References Anderson KB, Gibbons RV, Cummings DA, Nisalak A, Green S, Libraty DH, et al. A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand. J Infect Dis 2014;209(3):360–8. Balasingam S, Horby P, Wilder-Smith A. The potential for a controlled human infection platform in Singapore. Singapore Med J 2014;55(9):456–61. Bambery B, Selgelid M, Weijer C, Savulescu J, Pollard AJ. Ethical criteria for human challenge studies in infectious diseases. Public Health Ethics 2016;9(1):92–103. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 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(9951):1358–65. Cassetti MC, Thomas SJ. Dengue human infection model: introduction. J Infect Dis 2014;209(Suppl. 2):S37–9. Darton TC, Blohmke CJ, Moorthy VS, Altmann DM, Hayden FG, Clutterbuck EA, et al. Design, recruitment, and microbiological considerations in human challenge studies. Lancet Infect Dis 2015;15(7):840–51. Gordon SB, Rylance J, Luck A, Jambo K, Ferreira DM, Manda-Taylor L, et al. A framework for Controlled Human Infection Model (CHIM) studies in Malawi: report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi. Wellcome Open Res 2017;2:70. Guy B, Briand O, Lang J, Saville M, Jackson N. Development of the Sanofi Pasteur tetravalent dengue vaccine: one more step forward. Vaccine 2015;33 (50):7100–11. 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. Hodgson SH, Juma E, Salim A, Magiri C, Njenga D, Molyneux S, et al. Lessons learnt from the first controlled human malaria infection study conducted in Nairobi, Kenya. Malar J 2015;14:182. Hoffmann AA, Montgomery BL, Popovici J, Iturbe-Ormaetxe I, Johnson PH, Muzzi F, et al. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature 2011;476(7361):454–7. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. Antibodydependent enhancement of severe dengue disease in humans. Science 2017;358 (6365):929–32. 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. Larsen CP, Whitehead SS, Durbin AP. Dengue human infection models to advance dengue vaccine development. Vaccine 2015;33(50):7075–82. Low JG, Ooi EE, Vasudevan SG. Current status of dengue therapeutics research and development. J Infect Dis 2017;215(Suppl. 2):S96–S102. Low JG, Sung C, Wijaya L, Wei Y, Rathore APS, Watanabe S, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis 2014;14(8):706–15. Lyons AG. The human dengue challenge experience at the Walter Reed Army Institute of Research. J Infect Dis 2014;209(Suppl. 2):S49–55. Mammen MP, Lyons A, Innis BL, Sun W, McKinney D, Chung RC, et al. Evaluation of dengue virus strains for human challenge studies. Vaccine 2014;32(13):1488– 94. Nguyen NM, Tran CN, Phung LK, Duong KT, Hel Huynh A, Farrar J, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis 2013;207(9):1442–50. Nguyen TH, Nguyen HL, Nguyen TY, Vu SN, Tran ND, Le TN, et al. Field evaluation of the establishment potential of wMelPop Wolbachia in Australia and Vietnam for dengue control. Parasites Vectors 2015;8:563. Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T, et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N Engl J Med 2018;379 (4):327–40.
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79 Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, Coffeng LE, Brady OJ, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis 2016;16(6):712–23. Stunkel L, Grady C. More than the money: a review of the literature examining healthy volunteer motivations. Contemp Clin Trials 2011;32(3):342–52. Sun W, Eckels KH, Putnak JR, Lyons AG, Thomas SJ, Vaughn DW, et al. Experimental dengue virus challenge of human subjects previously vaccinated with live attenuated tetravalent dengue vaccines. J Infect Dis 2013;207(5):700–8. Torresi J, Ebert G, Pellegrini M. Vaccines licensed and in clinical trials for the prevention of dengue. Hum Vaccin Immunother 2017;13(5):1059–72. Vannice KS, Wilder-Smith A, Barrett ADT, Carrijo K, Cavaleri M, de Silva A, et al. Clinical development and regulatory points for consideration for secondgeneration live attenuated dengue vaccines. Vaccine 2018;36(24):3411–7.
S79
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(2):113–23. WER. Meeting of the Strategic Advisory Group of Experts on immunization, April 2018—conclusions and recommendations. . p. 329–44. Wilder-Smith A, Hombach J, Ferguson N, Selgelid M, O’Brien K, Vannice K, et al. Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine. Lancet Infect Dis 2019;19(1): e31–8. Winskill P, Carvalho DO, Capurro ML, Alphey L, Donnelly CA, McKemey AR. Dispersal of engineered male Aedes aegypti mosquitoes. PLoS Negl Trop Dis 2015;9(11) e0004156.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Bioethics of establishing a CHIM model for dengue vaccine development Anuradha Rose, Amrita Sekhar* Departments of Community Health, Bioethics, Christian Medical College, Vellore, Tamil Nadu, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 October 2018 Received in revised form 7 January 2019 Accepted 7 January 2019
Introduction: Controlled human infection models (CHIM) have been used in vaccine development to upselect and down-select potential vaccine candidates and to provide proof of vaccine efficacy, and have also been used as a basis for licensure of vaccines for cholera and typhoid by regulatory agencies. CHIM in dengue vaccines development: Dengue fever results in 400 million infections a year and is of significant health concern especially in India. There are currently no antivirals for the disease and the only licensed vaccine for dengue is not widely used owing to safety concerns. Controlled dengue human challenge models (DHCM) are currently being used to assess the efficacy of vaccines in development for dengue. Dengue CHIM in India: Conducting CHIM studies in India especially for evaluation of dengue vaccine candidates will be hugely beneficial as the disease is endemic to India and hence the effect of preexposure to the virus on vaccine safety and efficacy can be established. However, to date no CHIM studies have been conducted in India and there is a need to educate ethics committee members, policy makers and the public on the importance of such studies and what they entail. © 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Controlled human infection models Controlled dengue human challenge models Dengvaxia Dengue vaccine development
Introduction Dengue is a vector borne viral illness that results in 400 million infections a year. While most of these cases are asymptomatic, the burden of symptomatic dengue is estimated at 50–100 million infections per year (Stanaway et al., 2016). The disease spectrum in symptomatic dengue ranges from dengue fever which presents as self-limiting fever with rash, myalgia, arthralgia, thrombocytopenia and neutropenia to severe dengue resulting in vascular leak and shock. The development of vaccines and other therapeutics for dengue has been complicated owing to a multitude of factors including the lack of a known correlate of protection, complex and poorly understood disease pathogenesis resulting in various levels of disease severity, lack of a reliable animal model and the constantly changing viral landscape (Vannice et al., 2018). Several efforts have been made over the last few decades towards the development of dengue antivirals by targeting both structural and non-structural proteins of the dengue virus (DENV). Molecules targeting multifunctional enzymes NS3 and NS5, C
* Corresponding author at: Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, 632004, India. E-mail address: [email protected] (A. Sekhar).
protein, NS4B and those targeting viral entry have been explored (Low et al., 2017). Many drugs such as chloroquine, prednisolone, balapiravir etc. have been repurposed by researchers for dengue. However, though these drugs have been found to be safe, so for none of them have been effective for combating dengue (Low et al., 2014; Nguyen et al., 2013). Vector control efforts for dengue are centred around interventions that minimize oviposition sites of mosquitoes, insecticides which are applied on a rotation basis to prevent the emergence of resistance in the mosquito population, genetically modified mosquitoes which are sterile (Winskill et al., 2015) and the use of Wolbachia. Wolbachia, a bacterium, infects ovaries and testes of the Aedes mosquito and is able to alter host reproduction, thereby affecting the vector breeding cycle (Hoffmann et al., 2011; Nguyen et al., 2015). It also blocks the replication of the dengue virus (DENV) in the salivary gland of the mosquito. There are many ongoing efforts towards the development of dengue vaccines using different platforms technologies. So far the only vaccine for dengue; ‘Dengvaxia’ developed by Sanofi Pasteur was licensed in 2015 (Guy et al., 2015). This vaccine has been licensed by WHO and approved for use by the regulatory authorities in 20 countries in areas endemic for dengue for the age group 9–45 years. The other more advanced vaccine candidates which are in various stages of clinical trials include (Torresi et al., 2017); (a) TV003/TV005- developed by NIAID and the Butantan
https://doi.org/10.1016/j.ijid.2019.01.013 1201-9712/© 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
S75
Institute, (b) TDV- developed by Inviragen and Takeda, (c) TDENdeveloped by GSK and the Walter Reed Institute, (d) V180 developed by Merck and Hawaii Biotech and (e) DIME 100 developed by the US Naval Medical institute. Current efforts to manage the disease revolve around supportive care with an emphasis on close clinical monitoring especially during the critical phase of the illness and vector control to prevent disease spread.
subsided. For CHIM studies involving agents with known treatments, all volunteers whether they develop symptoms of infection or not are administered treatment after a pre-defined time-period. After this pre-defined period, volunteers are administered treatment whether they show signs of the infection or not.
Dengvaxia vaccine
Vaccine development for dengue has been extremely challenging for a multitude of reasons including the lack of a known correlate of protection and the lack of a correlation between clinical outcomes and the level of neutralizing antibodies. Controlled dengue human challenge models (DHCMs) can serve as a useful tool to up-select or down-select potential vaccine candidates before undertaking large scale clinical trials in dengue endemic regions. In addition, in the absence of a reliable animal model, a DHCM could also help in identifying a correlate of protection and expand our current understanding of the disease (Vannice et al., 2018). An ideal DHCM should have objective and reproducible endpoints and these end points should be reached without causing significant illness in volunteers Dengue human infection models have been used since the 1900s and have contributed to several insights on the disease including establishing it as a viral disease, defining the periods of incubation and infectivity of the virus in humans and mosquitoes, transmission patterns, clinical symptoms and features, homotypic immunity, cross protection, etc. (Cassetti and Thomas, 2014) There are currently two different DHCMs which are being used to evaluate vaccine efficacy. The first model (an infection model) uses a modified strain of the DENV-2 as a challenge strain (DEN2 D 30) and has been developed by NIH. When administered in challenge studies, this strain induces viremia in all volunteers, rash in 80% of the volunteers and neutropenia in 27% of the volunteers. Therefore, the primary end point used in this model to assess vaccine efficiency is viremia. The model induces mild clinical signs/ symptoms of dengue and lower levels of viremia which are highly reproducible. Additionally, as volunteers develop only mild symptoms of dengue (infection model) this model can be studied in an outpatient setting (Larsen et al., 2015). The second model developed by the Walter Reed Army Institute of Research (WRAIR) is a disease model. Initially, 7 strains of DENV of all four serotypes were tested in challenges studies and only DENV-1 and DENV-3 challenge strains were found to be suitable for use as defined by the clinical endpoint of dengue fever in infected individuals who were dengue naïve at the time of challenge (Larsen et al., 2015; Lyons, 2014). In this model, the subjects are monitored closely either in an inpatient/hotel setting for a period of 14 days post-challenge. The clinical end point is dengue fever which is defined as sustained fever (oral temperature >38 C for 48 h) accompanied by viremia (detectable by culture) with two or more of the following symptoms; headache, myalgia, erythematous rash, retro-orbital pain or arthralgia (Mammen et al., 2014). These two models have been subsequently used to evaluate vaccine efficacy of dengue vaccine candidates. In both models, the virus is administered parenterally, and the treatment involves the medical management of the symptoms The NIH model has been used to evaluate the efficacy of the TV003 vaccine candidate which is a live attenuated tetravalent vaccine particularly in those individuals who are seronegative to dengue prior to vaccination (Kirkpatrick et al., 2016). The study revealed that TV003 afforded complete protection after challenge with DEN2 D 30 administered 6 months after vaccination in dengue naïve volunteers. The Walter Reed model has been tested in volunteers who have been previously vaccinated with the tetravalent vaccine (Mammen
Dengvaxia CYD-TDV is a live-attenuated tetravalent vaccine which contains four recombinant live-attenuated chimeric viral vaccines on the yellow fever vaccine backbone. CYD-TDV was found to be safe and immunogenic in efficacy trials carried out in Asia and Latin America (Capeding et al., 2014; Villar et al., 2015). However, data from studies to assess the long-term safety of the vaccine revealed that three years post vaccination, the risk of hospitalization with dengue was higher in vaccine recipients as compared to controls and this risk was especially enhanced in children <9 years of age (Hadinegoro et al., 2015). Sanofi has since then conducted additional studies to ascertain the risk of the vaccine (Sridhar et al., 2018). The findings of their studies suggest that the vaccine behaves differently in individuals that are seropositive for dengue as compared to those that are seronegative for dengue at the time of vaccination, with seronegative individuals mounting varying levels of immune responses to the four serotypes. In seronegative individuals, the vaccine efficacy is lower, and they have an increased risk of hospitalized dengue and severe dengue from year 3 (after vaccination). The most probable explanation for this observation is antibody dependent enhancement with the vaccine mimicking the primary infection in seronegative individuals (Katzelnick et al., 2017). In the light of these findings WHO now recommends that countries considering Dengvaxia vaccination should have a prescreening strategy in which only dengue seropositive individuals are vaccinated (WER, 2018; Wilder-Smith et al., 2019). Controlled human infection models (CHIM) in vaccine development CHIM studies involve the intentional infection of a consenting healthy human volunteer with a virulent organism under controlled conditions. In a CHIM study, a well-characterized, attenuated and epidemiologically relevant strain of an infectious agent is administered in a controlled dose by a specific route to carefully selected and consenting healthy adult volunteers. The natural history of the infection, virulence, persistence in the body and the possibility of secondary infection are well established before the challenge strain is administered. In addition, the challenge strain is manufactured under Good Manufacturing Practice conditions. CHIM studies require skilled scientists, safe microbiology, excellent clinical facilities, and careful recruitment, monitoring and governance. CHIM studies in vaccine development are used to up-select or down-select potential vaccine candidates, test vaccine efficacy, reduce costs and accelerate the development of vaccines. In a CHIM study to test vaccines, volunteers are administered the vaccine and then infected with the infectious agent that they have been vaccinated against after a defined time period. They are then carefully monitored by trained health professionals and scientists, usually for a period of 10 to 14 days post infection for signs of viremia, infection etc. In all CHIM studies volunteers are followed up carefully until all detectable signs of infection (viremia/parasitemia etc.) have
Controlled human infection models in dengue and dengue vaccine development
S76
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
et al., 2014; Sun et al., 2013). In the challenge experiments, volunteers who had been previously vaccinated (between 8–42 months prior to challenge) were challenged with either DENV-1 or DENV-3 challenge strains. The study revealed that while all volunteers were immune to challenge through DENV-1 some volunteers developed dengue fever when challenged with DENV-3. This study further affirms the need to have long-term safety and follow up studies following large scale field efficacy trials. While both these models serve as useful tools to evaluate vaccine efficacy, they have their limitations. Since the NIH model is a model of infection and not disease it may not be well suited to provide information on severe forms of dengue pathogenesis and cannot be used to test therapeutics designed to address severe dengue. The Walter Reed model causes dengue fever and therefore requires it to be carried out in an in-patient setting with careful monitoring and clinical management. It has the potential to provide an understanding of more severe forms of dengue as well as help to evaluate therapeutics that modify the course of the illness. However, it may need more volunteers depending on how many actually meet the clinical end point of dengue disease when administered the challenge agent. So far, in both these models, challenge strains (based on failed vaccine candidates) have been developed for only a few serotypes; DENV-1 and DENV-3 in the Walter Reed model and DENV-2 in the NIH model. Another drawback of both these models is that since the virus is administered parenterally, the way the disease is induced differs from natural infection in terms of incubation period and the development of both innate and adaptive immunity. Despite these limitations, these models serve as extremely valuable tools to vaccine manufacturers in minimizing the risk of dengue vaccine development. The vaccine efficacy as determined by the dengue CHIMs still needs to be compared to that determined in classical Phase III trials. DHCMs can help supplement classical phase III studies for tetravalent dengue vaccines especially when efficacy cannot be demonstrated to all four serotypes due to a lack of naturally circulating strains to all serotypes. Conducting CHIM studies in India There are several advantages and reasons that support conducting CHIM studies in India. However, they require a consideration of several factors that need additional focus and monitoring as compared to more developed countries.
Building Indian research capacity: CHIM studies require rigorous research protocols and researcher sensitivity when dealing with volunteers. Both researchers and ethics committees (ECs) that review, permit and monitor these studies will need training. CHIM studies therefore provide an opportunity for India to ‘build local research capacities, clinical facilities, laboratory diagnostics, experimental medicine, clinical governance and regulatory confidence (Gordon et al., 2017). Scientific advancement for public benefit: CHIM studies can help accelerate drug and vaccine development and efficacy testing for diseases that are relevant to the national interest. Animal studies are sometimes inadequate in predicting human responses to interventions. The assessment of preliminary drug or vaccine efficacy could show that a candidate is likely to be ineffective thereby preventing unnecessary exposure of thousands of people in large Phase III trials. While for many diseases, it is unlikely that CHIM studies will replace Phase III trials, they would help in licensing a product followed by strict post marketing surveillance. CHIM studies have played a key role in development of vaccines against enteric diseases including the cholera vaccine Dukoral and typhoid vaccine Ty21a (Gordon et al., 2017). Risks and benefits in CHIM studies: CHIM studies carry different risk than other studies because the harm caused in them is intentional (Balasingam et al., 2014). However, the mere prospect of risk does not make a study unethical. In all types of studies, scientists plan for risks in order to protect participants and the community before they conduct the (Bambery et al., 2016) study. CHIM studies generally involve low risks because microbes used in the study are well characterized and the infection caused by the study can easily be managed. Furthermore, these studies include carefully considered and planned risk-mitigation strategies, monitoring and oversight that safeguard volunteer safety. Some argue that the risks undertaken by CHIM study volunteers is not more than that undertaken by volunteer firefighters or kidney donors. The benefits of conducting the study need to outweigh the risk to volunteers. In the absence of CHIM studies, more people are at risk of exposure to ineffective vaccines that can potentially cause harm in Phase III trials (Bambery et al., 2016). ECs in India need to be trained and sensitized to the risks posed by CHIM studies.
Ethics of CHIM studies
Infrastructure requirements
Local relevance: Currently, most CHIM studies are conducted in non-endemic countries where volunteers are typically college students from high-income countries who do not have the same genetic profile and pre-exposure environmental factors as an Indian resident. Therefore, conducting CHIM studies in India in a disease endemic setting makes the research more relevant to the local population. It allows for a better understanding of the effect of genetics, pre-exposure, immune status and environmental factors that may play a part in disease manifestation. Locally significant disease information could make drug or vaccine development more likely to succeed in the populations that need such interventions the most. The potential social and scientific benefits of indigenously developed drugs or vaccines to tackle diseases of public health importance in India is immense and there is a moral and public health necessity for locally conducted, locally relevant research. Development of vaccines and CHIM models for diseases not endemic to western countries by scientists in western countries may pose ethical problems, as the volunteers will be drawn from a population that will not benefit from the vaccine being developed.
Infrastructure and clinical facilities: The conduct of CHM requires the development of excellent infrastructure and clinical facilities. In India we currently may not be equipped to monitor adverse events during and after a CHIM study in any but a few clinical care settings. One proposal is to only allow renowned academic institutions to conduct CHIM studies so that issues of trust, control and scientific rigour involved in complex study designs are well balanced to protect the research participants. These facilities would need to be certified according to specific guidelines before the study can take place, and closely monitored. This is particularly important as study protocols for conducting established CHIM studies in India are likely to be very different than western countries. For example, in the UK, a typhoid challenge study is conducted in an out-patient setting where the volunteer returns home but has daily visits to the study centre for tests. However, in India given the varied and often inadequate sanitation infrastructure and hygiene practices, there might be a need to quarantine volunteers for the duration of the study to contain the pathogen and ensure that it does not spread to the community.
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
Challenge strain production: Infrastructure requirements also relate to the production of challenge strains. This would not be feasible without the proper facilities to assure quality, Good Manufacturing Practice (GMP) certifications, and a regulated delivery pathway to the volunteer.
Protection of volunteers and public engagement Fair selection: The strictest care should be taken to avoid exploitation, particularly of vulnerable members of society. While poverty and education should not be used to discriminate against those who desire to participate, in India, till clear protocols are made and the consent procedures are developed, only healthy, educated adults who are empowered to protect themselves should be included in a CHIM study. Informed consent: Special attention should be paid to creation of consent documents and procedures so that volunteers clearly understand what their participation entails. Volunteers and their families will require long and secure counselling before, during and after the study by a sensitive and well-trained multidisciplinary team. Research teams may need to continually assess volunteer consent after enrolling them in the study, recognizing that a volunteer has the right to discontinue participation at any time. Compensation: Participants will need to be compensated for their time spent in the study, which may cause loss of their regular wages and travel expense to the study site. In addition, if participants are in an in-patient facility, they should be compensated for the time away from their homes and families. Standard ways of compensating volunteers should be defined prior to starting the studies. In addition to this, as with all clinical research, compensation should be given in the event of adverse events. Care should be taken to design methods to ensure that the compensation does not cloud the decision of the participant to participate in the study. In a CHIM study conducted in Kenya, volunteers were offered financial compensation for transportation and time away from potential income generation opportunities or actual work. Participants were offered the idea of compensation, but the amounts were not disclosed till after the participants were enrolled in the study (Hodgson et al., 2015). Motivation for participation: Research has shown that participants are motivated by a variety of factors to participate in research involving risks (Stunkel and Grady, 2011) Therefore, efforts should be made to understand the motivations of the volunteer to participate in the study. The inclusion and exclusion criteria should include psychological preparedness of volunteers and their families. Public engagement: Researchers have highlighted the importance of understanding community perceptions of risk, disease severity, treatment availability and effectiveness of vaccines to prevent disease before designing CHIM studies (Gordon et al., 2017; Hodgson et al., 2015). Locally tailored consultation with and education of the public is essential to addressing anxieties that CHIM studies in the Indian context are likely to generate. Lessons from the experience of researchers in Kenya revealed that four years of stakeholder consultations greatly increased the understanding and acceptance of CHIM studies in their communities.
Regulations and governance The WHO Expert Committee on Biological Standardization, 2016 report titled, ‘Human Challenge Trials for Vaccine Development: regulatory considerations’, recognized that the regulation of
S77
CHIM trials need to be well defined by the national regulatory authorities and vaccine developers. In the US a CHIM study is subject to FDA regulations but in the EU, CHIM studies require Institutional Review Board approvals but not regulatory approvals (Balasingam et al., 2014). There are no comparable regulations in India as till date no CHIM study has been done in the country There is a need to develop a roadmap/guidance for conduct, review and monitoring of CHIM studies in India which should be endorsed by both the Indian Council for Medical Research (ICMR) and the Central Drugs Standards Control Organization (CDSCO), the national regulatory authority in the country before CHIM studies can be initiated in the country. At least initially it is very likely that CHIM studies in India will involve the import of challenge strains and therefore regulatory requirements and permissions for strain import will need to be carefully considered. Special ethical issues with DHCM studies As with all CHIM studies, the DHCM requires a careful consideration of risk-benefit, study design with respect to inclusion-exclusion criteria and carefully designed end points, challenge strain, informed consent, clinical facilities, and ethical, legal and regulatory requirements (Darton et al., 2015). However, the following points need to be carefully considered for a DHCM. Scientific validity In general, a dengue infection with a particular serotype of the virus results in the generation of homotypic serotype specific antibodies as well as heterotypic protective immunity from that serotype to other serotypes which is short lived (1.6 years) (Anderson et al., 2014). Therefore, the timing of challenge studies to evaluate vaccine efficacy is very important. If the challenge study is conducted soon after vaccination and within the window of heterotypic protective immunity, then it has the potential to provide misleading results especially on inferences made on the long-term heterotypic protection afforded by the vaccine (Vannice et al., 2018). The clinical end points need to be carefully defined in DHCMs in order for them to provide crucial information on the efficacy of therapeutics. For example, a clinical end point of viremia works well for the NIH model but for the WRAIR model dengue fever is a better end point. Social value The acceleration of production of an efficient vaccine will be of immense social value for a dengue endemic country with high mortality and morbidity rates. The previous studies and lessons learnt make it imminently possible to develop a good vaccine in a reasonable time frame using the DHCM. However, this should never be at the expense of participant safety and harm to participants. This is especially relevant in the light of the information provided by the studies on CYD-TDV. Risks Lessons learned from the studies on CYD-TDV have indicated that in the absence of previous dengue exposure the tetravalent vaccine partially mimics primary infection and therefore predisposes the vaccinated dengue naïve individuals to a greater risk of severe dengue on subsequent infection due to the presence of broadly cross reactive non-neutralizing antibodies (Sridhar et al., 2018). This is an important finding that needs to be kept in mind while designing DHCM studies. In the DHCM study of previously vaccinated volunteers with DENV-1 and DENV- 3 challenge strains,
S78
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79
the volunteers were first screened for the presence of neutralizing antibodies for the two serotypes to qualify for the challenge experiments (Sun et al., 2013). Establishing the sero-status of the volunteers through strict and rigorous inclusion and exclusion criteria is therefore crucial in dengue challenge studies. This is especially true in in dengue endemic countries where most people have had prior exposure to the disease. Dengue endemic countries should use the NIH model (infection model) in DHCM studies in order to ensure volunteer safety. This is especially important as there is no known treatment for the disease. All volunteers need to be followed up carefully after the study and any intervention tested and found to be beneficial should be administered to them.
Acknowledgements The authors would like to thank and acknowledge Ms. Gayatri Ganesh for her valuable contributions to this paper. Funding This article is part of a supplement entitled ‘Dengue Fever in India’ which is sponsored by the Department of Biotechnology, Government of India, and collated by the Translational Health Science and Technology Institute. Conflict of interest
Public opinion Outbreaks of dengue and media reports on mortality and poor responses from the medical sector has created a certain level of fear of the disease. Adequate community engagement and discussions with the public are essential to prevent public backlash against volunteers or health personnel involved in DHCM studies. This is especially important as there is no known treatment for the disease. Public harm The studies carried out thus far using DHCMs have been in areas which are non-endemic for dengue and therefore there is little risk for secondary transmission of dengue viruses in the community. However, if such studies are to be replicated in India and other endemic countries, they will have to be carried out under carefully controlled in-patient settings. Within these settings it is pertinent to ensure proper treatment and containment of patient samples and waste materials as well as deployment of appropriate mosquito control measures to safeguard against secondary transmission. This is especially important in India where access to general health care is not uniform across geographic locations and social strata. Participants should be followed up regularly for adequate periods of time. Plans for long term safety and surveillance should be carefully made. Any intervention which has been found to be effective should be provided to all volunteers after the study period. Conclusions DHCM studies have great advantages in terms of fast tracking a good vaccine for a disease which causes significant morbidity and mortality in endemic countries. The strains developed by NIH and WRAIR for dengue challenge studies have their inherent limitations. While significant care has been taken in these studies to minimize harm to the volunteers, future DHCM studies need to be designed very carefully especially in the light of the safety data from the CYD-TDV vaccine. Participant safety needs to remain at the forefront of such studies. In addition, while DHCMs offer many valuable insights into dengue and provide for the up-selection and down-selection of potential therapeutic targets including vaccines they are unlikely to serve as a replacement for a classical Phase III trial at least till the efficacy for a vaccine from both a DHCM and a Phase III trial can be compared. Meanwhile it is essential to invest in infrastructure development, and the training or researchers, ethics committee members and regulators in the ethics of CHIM and DHCM studies in order to be able to plan these studies in India in the future. Prior to planning DHCM studies, India should build expertise and experience in planning, conduct and supervision of CHIM studies by undertaking such studies on infectious diseases such as typhoid that are endemic to India and have wellestablished CHIM models with well-known treatments.
The authors declare no conflict of interest and no funding or ethics approval was sought for writing this review. References Anderson KB, Gibbons RV, Cummings DA, Nisalak A, Green S, Libraty DH, et al. A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand. J Infect Dis 2014;209(3):360–8. Balasingam S, Horby P, Wilder-Smith A. The potential for a controlled human infection platform in Singapore. Singapore Med J 2014;55(9):456–61. Bambery B, Selgelid M, Weijer C, Savulescu J, Pollard AJ. Ethical criteria for human challenge studies in infectious diseases. Public Health Ethics 2016;9(1):92–103. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 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(9951):1358–65. Cassetti MC, Thomas SJ. Dengue human infection model: introduction. J Infect Dis 2014;209(Suppl. 2):S37–9. Darton TC, Blohmke CJ, Moorthy VS, Altmann DM, Hayden FG, Clutterbuck EA, et al. Design, recruitment, and microbiological considerations in human challenge studies. Lancet Infect Dis 2015;15(7):840–51. Gordon SB, Rylance J, Luck A, Jambo K, Ferreira DM, Manda-Taylor L, et al. A framework for Controlled Human Infection Model (CHIM) studies in Malawi: report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi. Wellcome Open Res 2017;2:70. Guy B, Briand O, Lang J, Saville M, Jackson N. Development of the Sanofi Pasteur tetravalent dengue vaccine: one more step forward. Vaccine 2015;33 (50):7100–11. 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. Hodgson SH, Juma E, Salim A, Magiri C, Njenga D, Molyneux S, et al. Lessons learnt from the first controlled human malaria infection study conducted in Nairobi, Kenya. Malar J 2015;14:182. Hoffmann AA, Montgomery BL, Popovici J, Iturbe-Ormaetxe I, Johnson PH, Muzzi F, et al. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature 2011;476(7361):454–7. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. Antibodydependent enhancement of severe dengue disease in humans. Science 2017;358 (6365):929–32. 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. Larsen CP, Whitehead SS, Durbin AP. Dengue human infection models to advance dengue vaccine development. Vaccine 2015;33(50):7075–82. Low JG, Ooi EE, Vasudevan SG. Current status of dengue therapeutics research and development. J Infect Dis 2017;215(Suppl. 2):S96–S102. Low JG, Sung C, Wijaya L, Wei Y, Rathore APS, Watanabe S, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis 2014;14(8):706–15. Lyons AG. The human dengue challenge experience at the Walter Reed Army Institute of Research. J Infect Dis 2014;209(Suppl. 2):S49–55. Mammen MP, Lyons A, Innis BL, Sun W, McKinney D, Chung RC, et al. Evaluation of dengue virus strains for human challenge studies. Vaccine 2014;32(13):1488– 94. Nguyen NM, Tran CN, Phung LK, Duong KT, Hel Huynh A, Farrar J, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis 2013;207(9):1442–50. Nguyen TH, Nguyen HL, Nguyen TY, Vu SN, Tran ND, Le TN, et al. Field evaluation of the establishment potential of wMelPop Wolbachia in Australia and Vietnam for dengue control. Parasites Vectors 2015;8:563. Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T, et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N Engl J Med 2018;379 (4):327–40.
A. Rose, A. Sekhar / International Journal of Infectious Diseases 84S (2019) S74–S79 Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, Coffeng LE, Brady OJ, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis 2016;16(6):712–23. Stunkel L, Grady C. More than the money: a review of the literature examining healthy volunteer motivations. Contemp Clin Trials 2011;32(3):342–52. Sun W, Eckels KH, Putnak JR, Lyons AG, Thomas SJ, Vaughn DW, et al. Experimental dengue virus challenge of human subjects previously vaccinated with live attenuated tetravalent dengue vaccines. J Infect Dis 2013;207(5):700–8. Torresi J, Ebert G, Pellegrini M. Vaccines licensed and in clinical trials for the prevention of dengue. Hum Vaccin Immunother 2017;13(5):1059–72. Vannice KS, Wilder-Smith A, Barrett ADT, Carrijo K, Cavaleri M, de Silva A, et al. Clinical development and regulatory points for consideration for secondgeneration live attenuated dengue vaccines. Vaccine 2018;36(24):3411–7.
S79
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(2):113–23. WER. Meeting of the Strategic Advisory Group of Experts on immunization, April 2018—conclusions and recommendations. . p. 329–44. Wilder-Smith A, Hombach J, Ferguson N, Selgelid M, O’Brien K, Vannice K, et al. Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine. Lancet Infect Dis 2019;19(1): e31–8. Winskill P, Carvalho DO, Capurro ML, Alphey L, Donnelly CA, McKemey AR. Dispersal of engineered male Aedes aegypti mosquitoes. PLoS Negl Trop Dis 2015;9(11) e0004156.