Tuesday, January 19, 2016

Dengue Vaccine: To Vaccinate or not to Vaccinate, that is the question.

Dengvaxia (Sanofi Pasteur) is a live attenuated tetravalent chimeric vaccine made using recombinant DNA technology by adding the four serotypes of dengue virus into a yellow fever vaccine strain. There are ongoing phase III trials in Latin America and Asia involving over 31,000 children between the ages of 2 and 14 years. In the first reports from the trials, vaccine efficacy was 56.5% in the Asian study and 64.7% in the Latin American study in patients who received at least one injection of the vaccine. Efficacy varied by serotype. These are the preliminary only as the trails are still ongoing.
In both trials, vaccine reduced by about 80% the number of severe dengue cases. A closer look at the data shows that in Latin American and Asia at the 3rd year of follow-up showed that the efficacy of the vaccine was 65.6% in preventing hospitalization in children older than 9 years of age on the third year of followup. The response was greater in children who has been infected by dengue fever before (81.9%). The vaccine was approved in Mexico, Philippines, and Brazil in December 2015. Dengvaxia consists of three injections at 0, 6 and 12 months.

Other dengue vaccines may take a few more years to be available. Notable are DENVax (Inviragen/Takeda), TetraVax-DV (National Institute of Allergy and Infectious Diseases), TDENV PIV (GlaxoSmithKline) and V180 (Merck). DENVax looks promising as it combines dengue serotype 1,3 and 4 unto virus type 2 making it a purely dengue vaccine. It is being developed at Mahidol University in Bangkok. Currently all these are only in the phase 1 and 2 stages of development and it may be many years before it can be used.

There is a current dengue epidemic in many Asian countries with the number of cases and death increasing every month. Measures to control the vector, the Aedes mosquito, whether by reducing its breeding grounds, destroying the larvae, and killing of adults by fogging has not been proven effective in stamping the epidemic. Due to the ineffective measures, there is a loud public outcry and pressure on the respective governments to fast track the approval of Dengvaxia as what has happened in India where in January 2016, barely a month after the vaccine was approved for use in Mexico, Philippines and Brazil, the Indian government decided to waive a planned large scale trial and approve the use of the vaccine in the subcontinent. This means that India will not have any data on phase 3 and 4 clinical data conducted on her own people. The approval was based on phase 3 clinical data done in other countries. There always a risk when a new vaccine is introduced without adequate local data in a local population.

The WHO Strategic Advisory Group of Experts (SAGE) on Immunization is currently reviewing the evidence for Dengvarix and key considerations include vaccine safety, vaccine efficacy, disease burden, programmatic suitability, and cost-effectiveness. It is expected that it will submit its findings in April 2016. There is one major paper that describe the various trials done for Dengvaxia. It was published in New England Journal of Medicine on 24 September 2015. It collects data from various trials during a 25 month period (two years +one month). For a vaccine study, there is insufficient numbers and time for its true efficacy to be determined. There is also not much data to show whether people who received the vaccine may develop a more severe form of dengue when further infected. This could be the fastest record for a clinical paper to be published and the vaccine approved for use in Mexico, Brazil and Philippines. Other countries, for example Thailand (in which the 4 of the extension trials has been done) have not approved the use of the vaccine.

There is a dilemma here. On one hand, there is a full brown epidemic in progress. But this epidemic has been ongoing for many years so it may be call an endemic. On the other hand, there is a vaccine that is available though its true effectiveness is not really known. Furthermore, the safety profile, long term side effects and other side effects of this vaccine is also not known. There is not enough data available. Should we pressurize the Ministry of Health to approve this vaccine and allow its widespread use? The event of the Influenza H1N1 pandemic comes to mind. Because of the public outcry and panic, most governments stockpiled millions of dollars’ worth of Tamiflu, an antiviral agent. Tamiflu is not effective against H1N1. This is a known fact at the beginning of the pandemic. Yet that did not prevent governments from wasting their scarce resources from stocking up the antiviral agent.

In view of this dilemma, I will suggest two things. First, the Ministry of Health in cooperation with Sanofi to conduct a few large scale clinical trials of the efficacy and effectiveness of Dengvarix on Malaysians in Malaysia. This should give us the clinical data we need to make informed decisions about the vaccine. Second, we (the Malaysian public and healthcare professionals) should be patient and wait for the WHO recommendations that should be out in April this year. A point of note is that Brazil’s approval of the vaccine in December last year is conditional also to the WHO recommendation, which means it is not freely available in Brazil yet.

To conclude, when a fellow professional, who knew of my caution about using Dengvarix asked, “What will you tell your patient who is sick with dengue that you did not offered to give the vaccine?” My reply is that, “What will you tell your patient whom you had given the vaccine and come down with more severe form of dengue?”


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