At the Center for Infectious Disease Research (CIDR), we aim to develop safe and effective vaccines against infectious diseases by studying the interactions between invading pathogens and the human immune system, leveraging those discoveries toward the development of new vaccines.
We apply cutting-edge technology and systems biology approaches to decipher the critical interactions that can be targeted by potential vaccine interventions and to understand how pathogens interact with the host’s immune system. By studying these natural processes, we hope to gain a clear understanding of the mechanisms of protective immunity against these pathogens and how to re-elicit such immunity by vaccination. This strong scientific foundation enables us to take a rational approach to vaccine development, both in our efforts to develop new vaccine candidates and new vaccination approaches.
Our vaccine development efforts focus on HIV-1, TB, and malaria, diseases that affect millions of people around the globe and for which there are no vaccines capable of eliciting sterilizing immunity. Each of these diseases has unique challenges that make them exceedingly difficult targets for vaccine development. Malaria is caused by infection with Plasmodium parasites (Plasmodium falciparum chief among them), and has a complex, multi-stage life cycle, with each stage containing its own genetic program. Our vaccine development efforts are focused on two stages in the life cycle: the pre-erythrocytic and blood stages. However, because of its complex life cycle, very little is known about how malaria invades its hosts and establishes infection, and thus, few targets have been identified that can be utilized for vaccine development. Our researchers are working to identify the mechanisms of invasion by Plasmodium parasites and to understand how the parasite interacts with host target cells. These efforts have led to the identification of new potential vaccine targets and have assisted in the development of new types of vaccines.
In the pre-erythrocytic stages the parasite exists as a sporozoite, its infectious form that is injected into the skin during the mosquito bite. This stage is a desirable vaccine target, as interventions at this stage will prevent infection. Our scientists are pursuing multiple approaches to target the sporozoite stage. Professor Stefan Kappe has developed novel whole sporozoite vaccines in which he has disabled three genes that are critical for the establishment of blood stage malaria. This vaccine mimics natural infection in the early stages, allowing the immune system to learn how to recognize the infectious sporozoite. This promising vaccine is in the early stages of human clinical trials in the Malaria Clinical Trials Center at CIDR. Other efforts are underway to develop protein subunit vaccine candidates against the pre-erythrocytic and blood stages of malaria infection. Rather than presenting the immune system with the whole attenuated organism, this method chooses single protein antigens from the sporozoite or merozoite (the blood stage form) to be developed as vaccine candidates. This research is in the early stages, but several promising candidates are in various stages of pre-clinical evaluation.
Our HIV-1 vaccine development efforts take a similar approach to understanding host-pathogen interactions with the goal of informing vaccine design. Our researchers seek to understand how the host immune system is affected by HIV-1 infection and to understand how infection causes severe dysregulation within the host immune compartments. Using systems biology and classical immunological methods, our researchers are beginning to decipher how the host immune system senses the virus and how the virus modulates immune system signaling during infection. In addition, our researchers are beginning to understand how non-human primates infected with SIV, the simian version of HIV-1, are able to co-exist with the viral infection and remain healthy. These studies provide valuable insight into how the host immune system may need to be modulated during vaccination to elicit adequate immune responses. Finally, our researchers study how broadly neutralizing antibody responses develop in response to natural infection with HIV-1. These antibodies, which develop in some HIV-1 infected subjects, serve as a natural prototype of the types of antibodies that should be elicited by vaccination. Discoveries here at the Center have provided unique insight into how such antibodies develop during the early stages of infection and have led to the development of promising HIV-1 vaccine candidates.
Researchers at CIDR are also leveraging our technology and expertise to develop a safe and effective vaccine to prevent infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). The development of a vaccine against TB has been hampered by a poor understanding of how the pathogen remains in the body and evades the robust host immune response. Researchers at CIDR are working to understand why T cell responses during infection are unable to resolve TB infection naturally and are working toward an understanding of how natural host T cell regulation may enhance or restrict protective T cell responses. They've found that natural T cell regulatory networks may actually inhibit the clearance of TB during natural infection and may be a roadblock to eliciting long-lived resident T cell memory in the lungs. Overall, their goal is to develop a vaccine that will stimulate long-lived resident T cell-mediated protective immunity while avoiding harm to uninfected host cells.
At the Center for Infectious Disease Research, our approach to vaccine development is pushing the scientific envelope every day. Our unique combination of systems biology, immunology, and organismal biology creates an environment in which rapid and transformative discoveries are possible. This collaborative approach allows us to pursue discoveries that will enable us to tip the balance in the fight against these devastating diseases.