Conserved epitopes in Plasmodium falciparum and influenza A virus as targets for virus-vectored immunization
Embargo until
2015-05-01
Date
2014-01-28
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
The development of vaccines against infectious diseases has been highly successful. However, while effective vaccines have been licensed against many diseases such as smallpox, polio, measles, rubella, mumps, varicella, diphtheria, tetanus and pertussis, there are still a number of infectious diseases that continue to wreak havoc on public health. Many attempts have been made to create vaccines against intractable pathogens, such as HIV, malaria, and influenza A virus (IAV), but the construction of vaccines that induce broadly protective immunity against these diseases has proven difficult. This necessitates further research into conserved epitopes and new vaccine approaches.
In this study, I investigate the role of a highly conserved epitope of influenza A virus, the M2 extracellular domain (M2e), in the viral life cycle; this region has become a major molecular target for universal IAV vaccines. Using in vitro transcomplementation assays with cell lines stably expressing M2e mutants, we determined that this region of the M2 protein is tolerable of mutations since directed alanine mutagenesis nor deletion of several amino acids attenuated IAV replication. This suggests that this portion of M2e is not required for function and that alternative reasons exist for the high conservation.
In addition, the use of viral vectors for vaccines was investigated. Adenovirus (Ad) is a highly immunogenic viral vector. Recombinant Ads that display either the M2e or conserved HA2 alpha helix (HA2A) of IAV in hexon hypervariable regions were examined as potential universal influenza A vaccines. While these recombinant Ads were successfully created, they were not immunogenic in mice. Induction of effective immune responses by conventional vaccination methods is uncertain, especially for pathogens such as malaria and HIV. As an alternative to relying on an individuals’ immune system to mount a protective response, adeno-associated virus (AAV) was used to express previously characterized human broadly neutralizing monoclonal antibodies to the Plasmodium falciparum circumsporozoite protein (CSP) as a transgene. This ‘vectored immunoprophylaxis’ (VIP) approach allowed for rapid and high sustained expression of monoclonal antibodies to CSP that were capable of protecting mice from stringent sporozoite challenge, making this a viable approach for malaria prevention.
Description
Keywords
vaccine, virus-vectors