Sanofi Pasteur’s Dengvaxia was the first dengue vaccine to be licensed. Originally licensed in Mexico in December 2015, it is now licenced in 20 countries, according to the World Health Organization (WHO), for use in people aged 9 and 45 living in dengue-endemic areas. While safe for people who had previously been infected with dengue, the vaccine appears to put people who have never been infected at higher risk of more severe dengue. So, what was behind the vaccine’s strange behaviour? And what does it mean for dengue vaccination programs?

Essentially it comes down to a phenomenon known as antibody-dependent enhancement (ADE). The dengue virus has four serotypes, all of which can cause disease. Anyone catching dengue for the first time will develop antibodies with long-lasting protection against the infection’s serotype. They also develop antibodies that protect against the other serotypes – but that protection only lasts a short time. Once it wanes, that person will only have protection against the first (or primary) serotype.

Dengue and ADE

Imagine they then catch the virus a second time. Their pre-existing dengue antibodies would only stop the virus if the second infection were of the same serotype as the first. If not, ADE occurs. With ADE, these antibodies – being of a different serotype to the infecting virus – don’t neutralise it. Scientists believe that they instead bind to the virus and help it enter and infect the person’s cells.

What would most likely have otherwise been a mild viral infection becomes severe. In other words, the impact of the dengue virus can be more severe if you contract one dengue serotype, then a different dengue serotype.

An ideal dengue vaccine has to provoke the body to produce antibodies for neutralising all four dengue serotypes to avoid ADE. But research seems to show that, in people who have never had dengue, Dengvaxia may predominantly provoke the production of antibodies that protect against once specific serotype: DENV-4.

Dengue pre-vaccination screening

The WHO currently recommends pre-vaccination screening for dengue so the vaccine is only given to people who have previously been infected. It notes that “Decisions about implementing a pre-vaccination screening strategy will require careful assessment” and “Vaccination should be considered as part of an integrated dengue prevention and control strategy.”

Laboratory-based tests would be the most likely approach for dengue pre-vaccination screening; but processes can be time-consuming and these tests require a fair amount of laboratory resources. Researchers believe there may be delays of several days between sampling and receiving the result. Patients unwilling or unable to attend the clinic more than once (initially, for sampling and, secondly, for vaccination) would not get the protection they need.

Despite not being as accurate as laboratory tests, rapid diagnostic tests (RDTs) could allow prompt screening in areas where dengue is endemic. These areas often have limited resources, and laboratories may have limited capabilities and capacity. RDTs may also be useful in areas where transmission rates are high, which would benefit from immediate vaccination.

But RDTs are typically used for detecting current rather than past dengue infections. And while they have shown reasonable performance compared with laboratory-based tests, more research is needed. Current RDTs may need to be modified or new RDTs may be needed before they can be used in earnest for dengue pre-vaccination screening.

If you have been involved in a dengue pre-screening program, tell us about your experience.