Sanofi-Pasteur’s dengue vaccine shows promise, and an almost unhealthy dash of intrigue

Dengue virus, which is carried by insect vectors such as mosquitoes, represents a severe public health threat in an expanding number of countries, including South America, South-East Asia, Mexico and Africa. While the majority of individuals exposed to dengue virus recover unaided from often asymptomatic infections, a small number progress to very severe clinical manifestations, characterised by leaky vasculature and haemorrhage. Therefore, much effort is focussed on developing an effective vaccine for this infectious disease.

Dengue virus exists in four different serotypes (DENV-1, -2, -3 and -4), all within the flavivirus genus. If you become infected with one, you subsequently develop lifelong sterilising immune protection against that particular serotype. However, this protection does not extend to the other three dengue serotypes to which you were not exposed. In fact, infection with one dengue serotype followed by exposure to another manifests the most serious form of disease, dengue haemorrhagic fever. This implies that immune interplay and cross-reactivity between serotypes does not result in a healthy outcome, and that the goal of achieving a single effective dengue vaccine has some very elaborate immune intricacies to consider.

This complex immune dynamic appears to be one of the central difficulties recently encountered by the Sanofi-Pasteur dengue vaccine currently in phase IIb clinical trials in Thailand. The CYD-TDV vaccine (a recombinant live attenuated vaccine), administered as three doses over a 12 month period, develops balanced antibody responses against each of the four dengue virus serotypes, and protects on average 30% of patients. Intriguingly, if vaccine efficacy is analysed on the basis of dengue serotype, protection against DENV-1, -3 and -4 is very good (on average ~70%), but is incredibly poor (9.2%) against DENV-2, the serotype that most of the Thai children enrolled in this study were exposed to. This confounding evidence (poor vaccine efficacy in DENV-2-infected subjects despite the development of robust neutralising antibodies against DENV-2) could be explained through antigen mismatch, if the sequence of the DENV-2 antigen included in the CYD-TDV vaccine differed significantly from the strain of DENV-2 circulating in the geographical region of the trial. Alternatively, antibodies against dengue virus non-structural proteins (which are not included in the CYD-TDV vaccine) may have a hitherto unappreciated function in the development of robust, protective immunity.

You can read the original research article in full here.

Sabchareon A, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, Jiwariyavej V, Dulyachai W, Pengsaa K, Margolis HS, & Letson GW (2012). Dengue infection in children in Ratchaburi, Thailand: a cohort study. I. Epidemiology of symptomatic acute dengue infection in children, 2006-2009. PLoS neglected tropical diseases, 6 (7) PMID: 22860141

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