Exploring the role of a recently licensed dengue vaccine in Australian travellers

CYD‐TDV (Dengvaxia) use in travellers should be considered on a case‐by‐case basis, with a detailed discussion of risks and benefits in light of its safety and efficacy profile

Dengue has a significant impact on global health and is a leading cause of illness in travellers who visit dengue endemic countries. There are four serotypes of dengue virus, belonging to the Flaviviridae family, that are transmitted to humans by Aedes spp. mosquitoes. Infection with dengue virus can be asymptomatic or cause a self‐limited febrile illness, but can also cause severe infection. Secondary infection is a risk factor for severe dengue and one of the proposed mechanisms is antibody‐dependent enhancement of dengue infection. It has been shown that antibody‐dependent enhancement results from the presence of pre‐existing antibodies arising from a primary dengue virus infection that bind to an infecting dengue virus particle in a secondary infection with a different serotype. This results in an antibody–antigen complex that enhances virus entry and replication in monocytes and increases risk of severe illness.1 A key consideration for the development of an effective dengue vaccine has been how best to achieve efficacy against all four serotypes without significant safety concerns.

CYD‐TDV (Dengvaxia, Sanofi Pasteur) is the first dengue vaccine licensed for use in 20 countries in Asia, Latin America and Australia. CYD‐TDV is a tetravalent live attenuated chimeric vaccine administered as three doses (months 0, 6, 12) with no current indication for a booster dose. It is registered with the Australian Register of Therapeutic Goods but is not currently available in Australia, and can only be obtained on a case‐by‐case basis through the Therapeutic Goods Administration using the Special Access Scheme online system (https://www.tga.gov.au/form/special-access-scheme).

In phase 3 clinical trials, the vaccine has been shown to provide protection against dengue virus infection in dengue seropositive individuals, and reduce hospitalisations. However, long term safety analyses have raised concerns over its use in dengue seronegative individuals in endemic countries. The role of the vaccine in travellers needs careful consideration. The Australian Technical Advisory Group on Immunisation recently advised against the use of the vaccine in short term travellers and recommended limited use only in Australian travellers with past dengue infection, who are planning to reside in dengue endemic areas, if the risk–benefit consideration favours vaccination.2 This article considers the role of the vaccine for Australian travellers in the context of both the Australian Technical Advisory Group on Immunisation recommendations and the recently revised Strategic Advisory Group of Experts on Immunization (SAGE) recommendations on its use (Box 1).3

In July 2016, the World Health Organization endorsed the recommendation for the use of CYD‐TDV in people over the age of 9 years in regions with > 70% seroprevalence. The early findings of CYD‐TDV efficacy trials in individuals aged 2–16 years in the Asia–Pacific and Latin America regions underpinned the SAGE recommendation. The key findings of the trials were overall vaccine efficacy of 66% (notably lower efficacy for dengue virus serotype 2); reduction in severe dengue by up to 93%; and reduction in dengue hospitalisation by up to 82%.4,5

However, at the 3‐year follow‐up there was a clear trend, despite a low number of cases, of an increased risk of hospitalisation for virologically confirmed dengue in vaccine recipients in the younger age groups.6 This risk was most notable in Asian–Pacific children aged 2–5 years (relative risk [RR], 7.45; 95% CI, 1.15–313.80; although very wide due to the low number of cases, the confidence interval did not cross zero, indicating the trend of increased risk in vaccine recipients in the younger age group). Pooled risk estimates supported this observation with an RR of 1.58 (95% CI, 0.83–3.02) in vaccine recipients under 9 years of age compared with 0.57 (95% CI, 0.18–1.86) in children aged 9 years and older.6 At the 4‐year follow‐up, the trend of higher risk in the < 9 years age group, while less pronounced compared with the 3‐year follow‐up, was still present. In the immunogenicity subgroups which captured pre‐vaccination status of a small proportion of the study participants (7.5–20%, depending on the trial), a higher risk of hospitalised virologically confirmed dengue was apparent for seronegative vaccine recipients.7 Experts in the field raised concerns about the broader use of the vaccine in young children in endemic countries and highlighted the need for further examination of the role of age and pre‐vaccination serostatus with CYD‐TDV vaccination.8

A recent study added to the growing safety concerns by demonstrating that in seronegative vaccine recipients the risk of hospitalisation and severe dengue was higher than in individuals who were seropositive at baseline regardless of age.9 In this study, all cases of virologically confirmed dengue were reassessed for hospitalisation and severe dengue by serostatus and age groups. A subset of 10% (n = 3578) of the study participants underwent repeat testing with a novel non‐structural protein 1 (NS1) IgG antibody enzyme‐linked immunosorbent assay (ELISA) to determine their pre‐vaccination serostatus. Hospitalisation for severe dengue was increased in the younger age group of 2–8 years, with hazard ratios (HRs) of 1.95 (95% CI, 1.19–3.19) for hospitalisation and 3.31 (95% CI, 0.87–12.54) for severe virologically confirmed dengue in seronegative vaccine recipients versus unvaccinated controls. Similar increased risks of hospitalisation (HR, 1.75; 95% CI, 1.14–2.70) and severe virologically confirmed dengue (HR, 2.87; 95% CI, 1.09–7.61) were observed for seronegative participants aged 2–16 years. The increased risk of more severe infection in seronegative vaccine recipients was observed up to 30 months after vaccination. In contrast, vaccine efficacy in all age groups was significantly higher in seropositive individuals (76%) compared with seronegative individuals (39%).9 Based on these findings, the World Health Organization reconvened SAGE and in 2018 revised the recommendations for the use of CYD‐TDV (Box 1).3

In Australia, there has been a recent trend of increasing dengue notifications,10 with reports indicating that dengue infection is a leading cause of fever and illness in returning Australian travellers.11,12 Local dengue infection occurs in far North Queensland, but the introduction of a Wolbachia program in this region has led to a reduction in the annual outbreaks among local residents.13

For travellers visiting Bali, a common destination for Australians, a prospective study found that dengue occurred in 66.2% (133/201) of travellers who presented to a hospital with fever, and in that cohort, 13.5% were classified as having dengue haemorrhagic fever.14 In a study of Australian travellers returning from Bali, dengue was the most common laboratory‐confirmed diagnosis, reported in 5% of travellers.15 An effective and safe vaccine would therefore be a valuable addition to the pre‐travel vaccines offered to travellers. However, given the findings of the phase 3 clinical trials and the most recent SAGE recommendations, it would be essential to first determine whether a traveller can reliably report past dengue infection, with results from corresponding supportive diagnostic tests with high sensitivity and specificity for dengue, such as direct virus isolation, nucleic acid detection (polymerase chain reaction) or antigen detection (NS1 antigen assay). Without a clinical history or record to demonstrate past dengue infection, it is challenging to interpret positive dengue virus antibody serology in individuals who may have been previously infected with other flaviviruses, or received a vaccination (eg, yellow fever, Japanese encephalitis, Kunjin) that elicited cross‐reactive antibodies in dengue virus ELISA. NS1 IgG antibody ELISA assay overcomes the challenge of flavivirus cross‐reactivity but is currently not widely available.

Vaccination with CYD‐TDV for the prevention of primary infection with dengue is not recommended in travellers. In Box 2, we provide scenarios where vaccination can be discussed with dengue seropositive travellers who spend prolonged periods of time or intend to reside in dengue endemic countries; or who repeatedly and frequently travel to dengue endemic areas. In addition, the vaccine's long term efficacy (> 5 years) and long term risks associated with incomplete compliance to the schedule are not yet known. Another dengue vaccine, currently in phase 3 studies, may prove to be a more suitable option for travellers.16

Our recommendations are similar to those proposed by other experts.17 Despite CYD‐TDV being registered in Australia for use from July 2017, its use in travellers should be considered on a case‐by‐case basis, with a detailed risk– and cost–benefit discussion in light of its safety and efficacy profile.