I’m not a fan of baseball, either to play (too slow) or to watch (really too slow), but over its 150-year-plus history its enthusiasts have generated an interesting lexicon. A change-up pitch, as I learned from my more learned colleagues, is a slower-than-expected pitch that fools a batter into swinging early. In a mix metaphors, I note that we here in New England are experiencing a climatic change-up with warmer-than-expected winter and spring, and, while I realize that our local change-up is only a small piece of the global climate, my global health alarm rang when I read that the incidence of dengue fever has increased a whopping 30-fold since the 1960s (WHO fact sheet) and one factor in the increase may be increases in rain and temperature brought by climate change (Intergovernmental Panel 2007 report).
Dengue is a mosquito-borne viral infection that causes fever, headache, muscle and joint pain, and a characteristic rash and, in a small proportion of cases, develops into a lethal hemorrhagic form. WHO currently estimates there may be 50-100 million dengue infections worldwide every year and 15-25,000 deaths. It is a leading cause of death in children in some Asian and Latin American countries and is considered to have an impact on global health similar to tuberculosis. Defending oneself immunologically is challenging because there are four distinct, but closely related, serotypes of the virus and, while exposure to one provides immunity against that particular serotype, subsequent exposure to other types increases the risk of developing severe dengue (WHO fact sheet and Wikipedia article). So more water and warmth, more mosquitoes, and maybe more severe dengue. To add to the unpleasantness of dengue, there is no specific treatment and the carrier mosquito, Aedes aegypti, prefers to feed on human blood rather than that of other vertebrates. The best defense to date has been a good offense via mosquito control measures like insecticides, reducing standing water, and bed-netting. Dengue occurs in 110 countries, but in only a few places, like the US Gulf coast, have the control measures kept it completely under control.
It’s time for science to come to the rescue, and, as in the world’s response to HIV/AIDS, malaria, and tuberculosis but without the publicity and celebrities, researchers in academia, governments, and companies have been working on a vaccine. There are currently eight products in clinical trials sponsored by the NIH, Merck, Inviragen, GlaxoSmithKline, and Sanofi Pasteur (see Dengue Vaccine Initiative development). Sanofi’s ChimeraVax is in the lead with Phase III trials starting late in 2010 and a possible launch in 2014 (FierceVaccines article). The Sanofi vaccine is quite impressive technically in that it is a live, attenuated (infectious but not disease-causing), “recombinant” virus in which the envelope protein genes from the four types of dengue viruses have been used to replace the corresponding genes in the yellow fever virus (both are the members of the same viral genus) (Guy et al. 2011). And Sanofi has trod a long path, conducting trials in about 6000 persons in many countries (Mexico, Colombia, Brazil, Honduras, Puerto Rico, the Philippines, Indonesia, Vietnam, Singapore, Australia, Thailand, and Malaysia, Sanofi press release), and, at least according to its corporate responsibility site, is trying its best to have a successful launch: “Sanofi Pasteur collaborates actively with the WHO, national governments, payors, and NGOs (Dengue Vaccine Initiative, Bill and Melinda Gates Foundation, Sabin Institute, etc.). These efforts aim to reduce insofar as possible any delays that might stand in the way of introducing the vaccine quickly once it has received authorization from national authorities” (Sanofi CSR). But, as it is well-known, it is the pioneers that get shot by the arrows, and it will be interesting to see if Sanofi can avoid being scolded or worse by the various global health “advocacy” groups as it tries to recoup its substantial investment in a vaccine for a disease with almost no first world market.
Several problems loom. One is Sanofi meeting demand for the vaccine. The company has built a new plant with a 100 million dose per year capacity, but a study by the International Vaccine Institute estimnated an “upper limit” need of about 600 million doses per year for the first five years (3 doses given over 12 months to children under the age of 12 years, Amarasinghe et al. 2010). A second loomer is that of pricing which Sanofi is likely negotiating with potential buyers now, but very quietly. Third, the success of any vaccination program depends heavily on other players like governments, donors, and NGOs to:
-gather epidemiologic data that are needed to vaccinate the right populations;
-include the vaccine in national vaccination, control, and awareness programs; and, of course,
-pay by financing the budget needed for consumables, infrastructure, and training.
Lastly, Sanofi has a substantial task in conducting Phase IV trials to monitor safety, since there is a small possibility that the vaccine may mutate to a virulent form or increase the chance of the natural virus causing the hemorrhagic syndrome (Guy et al. 2011). In the self-promotion department, I note that I think one of the key executives navigating these shoals is Alan Watson, Sanofi’s vice president for Vaccination Policy and Advocacy, who has kindly accepted my invitation to participate in a panel I am organizing for BIO 2012 called “Accelerating Access Public Sector Markets” (June 18 at 3:30 PM if you are there). And the effect of the climatic change-up on the use of vaccines to reduce the impact of dengue is unknown.
Historical footnote: the route from ChimeraVax concept to product has been a long one. In the late 1990s, the idea and technology was invented by Thomas Chambers of St Louis University and scientists at OraVax, a Cambridge, MA, company founded in 1990. Shortly OraVax licensed the university’s rights in 1999 (PR Newswire story), it was acquired by Peptide Therapeutics of Cambridge, UK, and the joint company was renamed Acambis (Inknowvation entry). Acambis successfully completed a Phase I clinical trial of the dengue vaccine in 2002 (Vacination News article), I was interviewed but not hired for an Acambis business development position in 2005, and Sanofi partnered with Acambis on its ChimeraVax vaccine for West Nile fever in 2007 (FierceBiotech article) and acquired the company for $565 million in 2008 (another FierceBiotech article).