Live attenuated vaccines contain weakened forms of the virus. The goal is to vaccinate with a weak form and elicit an immune response in the individual being vaccinated without causing disease. Live attenuated vaccines have been successfully developed for yellow fever and Japanese encephalitis, which, like dengue, are flaviviruses. The challenge with dengue is to develop a vaccine that is safe and effective against all four dengue serotypes – referred to as a tetravalent vaccine. Yellow fever and Japanese encephalitis vaccines need to protect against only one serotype.
Dengue vaccine strains can be attenuated through a number of different means. The earliest attempts at developing a vaccine for dengue, starting in the 1920s and 1930s, involved attenuating the virus by repeated passages through animal cells or mixing with ox bile. More recent methods include passage through animal cells, and recombinant genetic technology. Several companies are developing vaccines based on genetic engineering. The attenuation of virus to create live attenuated vaccines through reverse genetics technology, and introduce targeted mutations, represents the most advanced approach.
Live Attenuated - Chimerization
Chimeric vaccines are created by cloning pieces of one virus into another virus and deriving a “chimer.” Here, yellow fever virus is used as a replicative backbone but carries the structural proteins of dengue virus, forming a chimeric structure. The most clinically advanced dengue vaccine candidate is the yellow fever/dengue chimeric vaccine (CYD), initially developed by Acambis and now by Sanofi Pasteur. The vaccine is based on a yellow fever vaccine strain genomic backbone with substitutions of two genes encoding dengue proteins, and is being studied extensively in non-clinical and clinical studies. A Japanese encephalitis vaccine developed by Sanofi and based on similar technology has recently received approval.
Sanofi is currently conducting a Phase 3 trial of its dengue vaccine candidate, with three doses of the vaccine given over the course of a year, in countries in Asia, in Australia, and in countries in Latin America. First results of a Phase 2b efficacy study in Thailand showed the vaccine was safe, though poorly effective – failing to protect against DEN-2 and showing only a 30% effectiveness (percent of people protected) overall against all serotypes, with a large variation in protection between serotypes. The Phase 3 result will allow for a full evaluation of vaccine efficacy.
Progress is also reported on a chimeric dengue-dengue vaccine built on the DEN-2 PDK53 strain as vaccine vector, a strain originally developed by DVI’s Senior Scientific Advisor, Dr. Scott Halstead. Led by Inviragen (recently acquired by Takeda), in collaboration with the U.S. CDC, the University of Wisconsin, and Universidad de Antioquia in Colombia, the vaccine has entered Phase 2 clinical trials in Puerto Rico, Colombia, Singapore and Thailand. The vaccine is given as two doses three months apart. In addition, strategies to reduce the interval between doses and needleless administration are being investigated.
Live Attenuated – Sequence Deletion
The U.S. National Institutes of Health (NIH) live attenuated dengue vaccine is comprised of the four dengue virus serotypes, each attenuated by removing a small part of the virus. The NIH tested different monovalent dengue vaccine candidate vaccines in healthy flavivirus-naïve adults (i.e. not previously exposed to flaviviruses) to select those candidate vaccines with the most favorable safety and immunogenicity profiles. Six different monovalent vaccines were evaluated in four different tetravalent admixtures given to flavivirus-naïve healthy adults to determine which admixture induced the highest seroconversion (development of antibodies) rates to each of the four dengue serotypes. TV003 was chosen as the candidate for further evaluation. TV003 is currently being evaluated in flavivirus-experienced (i.e. previously exposed to flaviviruses) adults in the U.S. and will begin Phase 2 evaluation in Thailand in flavivirus-experienced adults and children.
The NIH strains have also been licensed by the U.S. NIH to several developing country manufacturers on a non-exclusive basis.
- The Insitituto Butantan (Brazil) has produced clinical lots of their live attenuated tetravalent vaccine (licensed NIH vaccine). They have received approval to begin Phase 2 testing of this product in flavivirus-naïve and flavivirus-experienced adults in Brazil.
- Vabiotech (Vietnam) has licensed the NIH vaccine candidate TV003 and has started production of the monovalent seed lots. When those have completed safety testing, they will formulate a live attenuated tetravalent vaccine. They are developing their clinical trial plan.
- Panacea Biotech (India) has produced different lots of their live attenuated tetravalent dengue vaccine (licensed NIH vaccine) formulation and completed stability testing on these lots.
Biological E (India) has made seed lots at scale of their live attenuated tetravalent dengue vaccine (licensed NIH vaccine) and are reviewing their clinical development strategy.