dengue vaccine

industry-sponsored study in the lancet of a new dengue vaccine (see dengue vaccine lancet 2014 or doi.org/10.1016/S0140-6736(14)61060-6). background (in brief):
    
    --50 million infections/year in 100 countries (though some report 390 million cases/yr with 96 million having clinical disease), now including florida and texas areas
    --mosquito vector (aedes aegypti and a. albopictus). spread of disease associated with globalization (transport of mosquito vectors as well as infected people), urban crowding, ineffective mosquito control strategies, and (likely) global warming. 
    --4 serotypes (types 1-4). these are present in all regions, with changing frequency of the different serotypes within the same country

lancet study:
    --phase 3 trial of vaccine efficacy. RCT in 5 countries in Asia-Pacific region (indonesia, malaysia, philippines, thailand, vietnam), where 70% of the global dengue cases occur. tetravalent recombinant live-attenuated vaccine (CYD-TDV) given at months 0, 6, 12. 
    ​--primary objective: assess protective efficacy against symptomatic, virologically-confirmed dengue at least 28 days after 3rd shot. 25 month follow-up. 
    --10275 children aged 2-14 randomized to vaccine or placebo in 2:1 ratio. 250 cases of virologically-confirmed dengue developed (4.7% of the kids, highest in the philippines and thailand)
    --vaccine had 56.5% efficacy overall. 
    --efficacy higher in kids with pre-existing dengue neutralizing antibodies than those seronegative, in older than younger ages (33.7% in those 2-5 years old vs 74.4% in those 12-14). small differences by country (from 51.1% in vietnam to 79.0% in malaysia)
    --28 (5%) of the confirmed cases had dengue hemorrhagic fever, 8 in the vaccine group and 20 in the control group (but there were twice as many kids in the vaccine group with the 2:1 randomization), so that vaccine efficacy against hemorrhagic fever was 80% after only 1 injection and 88.5% after 3 injections. overall milder cases in the vaccinated group (eg, fewer hosp admissions and length of stay)    
    ​--pretty dramatic differences in efficacy by serotype: from nonsignificant 35% efficacy in serotype 2 infections, to (all significant) 50% for serotype 1, 75.3% for serotype 4 and 78.4% for serotype 3 (the most common infection was with serotype 1 (51 cases), followed by serotype 2 (38 cases), serotype 4 (17) and serotype 3 (10) -- these differences in serotype efficacy explained the differences in vaccine efficacy in the different countries.
    --647 adverse events (402 in vaccine group and 245 in controls), with not much difference between groups

so, pretty impressive results for serotypes 1,3,4. unclear why no response to serotype 2 (mean titers were actually higher for 2 than the other serotypes), though a prior study in thailand which did not find the vaccine to be effective was likely because of their predominance of serotype 2. particularly notable is the decrease in disease severity. though the vast majority received 3 shots, those who received only one had pretty much the same efficacy (may be related to the fact that so many had already had dengue before, and the vaccine provided priming effect). this finding, as well as the fact that the vaccine worked best in those who already had neutralizing antibodies and in older kids, suggests that the primary utility of the vaccine may be in those who already had infection and therefore some pre-existing immunity, and that the target of the vaccine might be in the highly-endemic regions.

NEJM had a good clinical review of dengue (see dengue review nejm 2012 in dropbox, or N Engl J Med 2012;366:1423-32)

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