Novel Vaccines for Measles
Investigator:
Background:
Despite reaching global measles vaccination coverage of >80% of individuals, measles remains one of the leading causes of death in children under 5 years of age. In 2001, an estimated 31 million cases of measles occurred globally resulting in 777,000 deaths mainly in sub-Saharan Africa. Implementation of WHO/UNICEF measles mortality reduction strategies helped to decrease mortality rate to 242,000 deaths in 2006.
There are several limitations of the licensed measles vaccines. First, live attenuated measles vaccines are inactivated by light and heat and lose about half of their potency after reconstitution if stored at 200C for one hour; therefore, a cold chain must be maintained. Second, measles vaccines must be injected subcutaneously or intramuscularly, necessitating trained healthcare workers, needles, syringes and the proper disposal of hazardous waste. Third, maternally acquired antibodies reduce the protective efficacy of the vaccines in early infancy, hindering effective immunization of young infants. Fourth, live attenuated measles vaccines have the potential to cause serious outcomes, such as lung or brain infection, in severely immunocompromised individuals. Fifth, two doses of the vaccine must be administered to achieve sufficient levels of population immunity to interrupt measles virus (MV) transmission. Finally, live attenuated measles vaccine can not be used in the general population after global eradication of the wild-type virus. Therefore, we proposed to develop and test two new vaccine candidates based on adenoviral vector and recombinant proteins (a subunit vaccine).
Objectives
- Construct recombinant adenoviruses expressing genes for MV F and H.
- Produce ectodomains of the F and H proteins in a mammalian cell expression system (subunit vaccine) and formulate the subunit vaccine with novel adjuvants.
- Test the immunogenicity of the novel vaccines in mice.
- Evaluate the immunogenicity and protective efficacy of the novel vaccines in naïve cotton rats and in cotton rats with passive MV-specific neutralizing antibodies.
Progress
The synthetic codon-optimized MV F and H genes were were cloned into pH5-L vector for construction of recombinant E1-deleted human Ad-5 and into pProtA-IRESpuro vector to express secreted version of the proteins fused with a protein A tag in cell culture. The recombinant human adenoviruses expressing MV genes were constructed after transfection of HEK293 cells with the plasmids containing Ad5 genomic DNA. Also, expression of the secreted MV F and MV H was demonstrated in the cell culture medium of HEK293 cells transfected with pProtA-IRESpuro vector-based plasmids.
