Vaccination perspectives: the Qdenga® dilemma

In May 2024, a second vaccine for dengue (TAK-003 or Qdenga®) received World Health Organization (WHO) prequalification. This live attenuated tetravalent dengue vaccine designed to protect against all four serotypes of the dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4) has been introduced in routine immunization programmes in some countries where the high transmission intensity of dengue poses a significant public health problem. Some non-endemic countries have also adopted it as a traveller vaccine.¹

TAK-003 will have a positive impact in high-transmission intensity settings, however its use in travellers from non-endemic countries has created much debate, not least because of experiences with the first dengue vaccine (CYD-TDV or dengvaxia). Introduced in 2015, dengvaxia is restricted to those previously infected with dengue in endemic regions. Specifically, the need for a pre-vaccination screening strategy has limited its use in national immunization programmes. Conversely, licensure of Qdenga® is less prohibitive. Of note, while both vaccines are tetravalent live-attenuated vaccines, they differ in the extent of chimerization and the genome backbone, as well as in efficacy and safety.^1,2

For TAK-003, evidence suggests those previously infected with any dengue virus serotype may benefit from vaccination to prevent a second (and potentially more severe) infection if travelling to endemic areas, but for travellers who have never experienced dengue infection (‘dengue-naïve’ individuals) the benefits are lower. In particular, the vaccine may not confer protection against DENV-3 and DENV-4 in dengue-naïve individuals, and may potentially pose a risk of severe dengue if they are subsequently exposed to these serotypes.²

This paper provides an overview of the epidemiology of dengue, the approach of different countries on use of Qdenga® in travellers (table 1), and how these translate into clinical practice.

Epidemiology

The epidemiology of dengue has seen substantial increases in reported cases globally since 2019, with an acceleration in numbers of cases since 2022 (WHO, https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON475). It is recognized that the global burden of dengue, along with the incidence and impact in travellers is likely to be underestimated. Furthermore, occasional transmission of dengue within countries in Europe has been reported in recent years, reflecting the establishment of the vector Aedes albopictus in parts of Europe.³

Among travellers, those visiting friends and relatives (VFR) and spending longer periods in endemic areas, particularly those with strong ties to diaspora communities, are often considered to be most likely to acquire a dengue infection. However, studies have shown that all travellers to dengue endemic countries including those travelling for leisure are at risk of acquiring infection, with multiple factors impacting the level of risk.^4,5

Dengue is not endemic in the UK, but in 2023, 634 cases were reported in England, Wales and Northern Ireland (UKHSA, Travel-associated infections in England, Wales and Northern Ireland: 2023 Available from: https://www.gov.uk/government/publications/travel-associated-infections/travel-associated-infections-in-england-wales-and-northern-ireland-2023#dengue). All cases were acquired during international travel, with the majority associated with travel to Asia. Often travel was to countries with historical, economic, and cultural ties with the UK (fig. 1).

Translating evidence into practice

Since Qdenga® was granted marketing authorisation in the EU and UK, guidance on its use in travellers has been issued in many countries (Table 1). While the licensing authorities in the EU and UK did not stipulate any specific restrictions on the use of the vaccine for those over the age of four years, the recommendations made by public health bodies or expert groups have in general been more cautious. The legal basis for these recommendations varies according to jurisdictions, and is beyond the scope of this article, but it is assumed that in most countries, recommendations are intended to guide rather than mandate specific actions.

All parties listed in Table 1 agree that Qdenga® may be recommended for those travelling to dengue endemic areas who have had previous dengue infection. They also agree that meticulous mosquito bite avoidance measures are necessary, as Qdenga® vaccine does not offer 100% protection against dengue infection.

Most acknowledge that Qdenga® efficacy against serotypes DENV-3 and DENV-4 in dengue-naïve individuals was not established due to lack of data,² and some, while accepting that circulating serotype information at the traveller’s destination could help inform vaccine decision-making, recognize the impracticality of this approach due to unavailability of such detail and the possibility of multiple serotypes co-circulating.²

Most parties recommend use of the vaccine from four years of age, but at least one group aligns with the WHO recommendation of a higher age limit of six years; based on the possibility of reduced efficacy in four and five year olds.²

Similarly, another group advises that Qdenga® is not recommended for those over 60 years of age; consistent with WHO recommendation based on lack of efficacy data in this age group.²

The main challenge in formulating policy relates to whether vaccine should be offered to dengue-naïve travellers due to the theoretical concern of an increased risk of severe infection if exposed to DENV-3 or DENV-4 following vaccine.²

For clinicians, central to the dilemma is the question: which poses the greater risk to dengue-naïve travellers, the theoretical risk of an adverse event following Qdenga® vaccination, or a dengue infection, which rarely causes serious illness or death in travellers?⁶

Consequently, recommendations, while broadly similar, have nuanced differences, not only on who should be vaccinated, but also on how to identify prior dengue infection. Differing guidance is commonplace in travel medicine; variation in international recommendations exist for many reasons; product availability, health systems delivery, governance frameworks or regulatory standards, traveller patterns and risk tolerance to name a few.⁷

Of note a minority of parties state that Qdenga® can be offered to travellers regardless of whether they have had dengue infection previously, although there may be restrictions imposed based on the type of travel. Others advise that some dengue naïve individuals may be offered vaccine depending on for example travel plans, age or individual vulnerabilities, and some recommend that Qdenga® is only offered to those with a confirmed previous dengue infection. Many travellers, however, are unaware of whether they have had dengue in the past, particularly if infection was asymptomatic/mild. Guidance on what would constitute evidence of previous infection varies between countries and could include a compatible history of dengue infection and/or laboratory confirmed tests.

Previous dengue infection can only be reliably confirmed if the traveller was tested at the time of illness, and therein lies the challenge for those advising travellers; using dengue virus serology to identify past dengue infection and the cross-reactivity of other flavivirus infections and vaccinations (Zika, tick-borne encephalitis, yellow fever etc) means that results must be interpreted with caution and in combination with a compatible history of travel and previous dengue like illness. It could be argued that negative serology may help a more hesitant traveller chose not to have the vaccine, or encourage a frequent or longer-term traveller to an endemic area to have testing in country during a dengue-like illness.

Enabling travellers to make informed healthcare choices is fundamental to our work, but how do we enable travellers to make choices in the context of uncertainty regarding safety, the challenges of demonstrating previous infection, and differing international guidelines?

What is clear is that the benefits of vaccine are likely to outweigh the risks for those travellers who have had a previous dengue infection. However, to withhold Qdenga® from travellers who are dengue-naïve may seem counter-intuitive to the traveller, as typically vaccines are offered to protect against infection before first exposure and not increase the risk of severe infection. Furthermore, restricting vaccine use may be contrary to the traveller’s expectations; the chance of disruption to a once in a lifetime holiday by a relatively mild illness may eclipse their concerns about theoretical vaccine safety. Add to this, the cost of accessing healthcare, disruption to travel itineraries, and loss of income (estimated at an average total out of pocket cost of US$992 per dengue episode in one study),⁸ the cost benefit analysis may shift in favour of vaccination for some travellers.

The decision to offer vaccine ultimately rests with the clinician in discussion with the traveller. Many factors will influence this discussion, but trust in the importance, safety, and effectiveness of vaccines are key; experience from the use of dengvaxia has highlighted that a dengue vaccine with a potential risk of causing more severe disease, even in a small proportion of individuals, requires careful communication.⁹ Key to this, in the travel clinic setting will be shared decision-making to ensure the traveller understands the risks, benefits and possible consequences of different options through detailed discussion and information sharing; it is not sufficient to simply say there is an absence of efficacy data.²

Conclusion

A new vaccine against dengue is welcome, both in dengue-endemic countries and among travellers. However, there is a debate surrounding the use of Qdenga® in travellers based on potential safety issues and questions around vaccine efficacy (VE) in different traveller groups.

Guidelines express caution in the use of Qdenga® in dengue-naïve travellers (likely to include most travellers from non-endemic countries), due to reduced VE in this group and the theoretical increased risk of severe dengue if infected with DENV-3 or DENV-4 following vaccination, through antibody-dependent disease enhancement (ADE). This is an evolving situation; it is reassuring that in clinical trials of the vaccine; now at least 4.5 years from the receipt of the second dose in many trial subjects (4–16 year-old children in endemic regions) there has been no indication of ADE with a subsequent infection.

However, due to a lack of clinical trial data, questions remain over the efficacy of the vaccine in younger children and adults over the age of 60. Further clinical trials are urgently required in these groups and rigorous post-licence surveillance should be aimed at establishing the safety and efficacy of the vaccine in different traveller groups in the ‘real-world’ setting.

Consideration should also be given to whether those most likely to benefit from the vaccine, for example those long-stay VFR travellers, will request Qdenga®? These travellers may assume they have some degree of immunity to familiar infections and may be reluctant to receive a vaccine they feel is unnecessary. Cost of the vaccine will also play a part; it may become unaffordable if there is an additional charge for serological testing particularly if the results do not assist in clinical decision making. Conversely the dengue-naïve traveller going on an expensive luxury trip or business trip may wish to prioritize the risk of illness disrupting their holiday or work over the theoretical risk of severe dengue. Communication is key to helping these travellers understand the potential risks and benefits of Qdenga® and to ensure that it is offered to those travellers most likely to benefit from it.

Early data from post marketing studies in dengue naïve and older travellers is now emerging.¹⁰ How this will impact on timelines for changes in recommendations remains unclear, and will likely vary due to complexities and variations in data interpretation and risk tolerance.

Funding

There was no funding for this paper.

Author contributions

Fletcher, Rachael Conceptualization (Lead) Project administration (Lead) Writing—original draft (Lead) Writing—review & editing (Lead).

Richards-Zoubir, Samia Conceptualization (Equal) Data curation (Lead) Formal analysis (Lead) Project administration (Equal) Writing—review & editing (Equal).

Koopmans, Imogen Conceptualization (Equal) Data curation (Equal) Investigation (Equal) Writing—original draft (Equal) Writing—review & editing (Equal).

Smith, Catherine C Conceptualization (Equal) Investigation (Equal) Writing—original draft (Equal) Writing—review & editing (Equal).

Veal, Philip Conceptualization (Equal) Investigation (Equal) Writing—original draft (Equal) Writing—review & editing (Equal).

Patel, Dipti (Corresponding Author)Conceptualization (Lead) Formal analysis (Equal).

Investigation (Equal) Writing—original draft (Lead) Writing—review & editing (Lead).

Rachael Fletcher (Conceptualization-Lead, Project administration-Lead, Writing—original draft-Lead, Writing—review & editing-Lead), Samia Richards-Zoubir (Conceptualization-Equal, Data curation-Lead, Formal analysis-Lead, Project administration-Equal, Writing—review & editing-Equal), Imogen Koopmans (Conceptualization-Equal, Data curation-Equal, Investigation-Equal, Writing—original draft-Equal, Writing—review & editing-Equal), Catherine Smith (Conceptualization-Equal, Investigation-Equal, Writing—original draft-Equal, Writing—review & editing-Equal), Philip Veal (Conceptualization-Equal, Investigation-Equal, Writing—original draft-Equal, Writing—review & editing-Equal), Dipti Patel (Conceptualization-Lead, Formal analysis-Equal, Investigation-Equal, Writing—original draft-Lead, Writing—review & editing-Lead).

Conflict of interest: The authors have declared no conflicts of interest.

Data availability

The datasets were derived from sources in the public domain: https://www.gov.uk/government/publications/travel-associated-infections/travel-associated-infections-in-england-wales-and-northern-ireland-2023#dengue  https://www.ons.gov.uk/peoplepopulationandcommunity/leisureandtourism/datasets/travelpac.

References