Dissecting the host immune response to bacterial and HIV carbohydrate antigens to guide vaccine design

Vaccines are important for preventing the spread of disease. Successful vaccines prepare the body's immune system to fight potentially deadly diseases by producing proteins called antibodies that identify and kill disease-causing agents like viruses and bacteria. Many infectious agents have carbohydrate structures on their surfaces. The bacterial vaccines used routinely to vaccinate infants work by producing antibodies that bind the specific carbohydrates on the bacterial surface. In addition, my previous work has also shown that a small number of HIV-infected patients produce antibodies that bind the carbohydrates on the virus surface and kill HIV. These observations suggest that vaccines designed to produce carbohydrate-binding antibodies could be successful at controlling disease spread. The aim of this project is to understand how the body makes these carbohydrate-specific antibodies during HIV infection and following vaccination with bacterial vaccines so that new vaccines can be made. This work will involve the isolation of carbohydrate-specific antibodies from HIV-infected patients and from individuals vaccinated with bacterial vaccines. I will determine what the antibodies look like and which carbohydrates the antibodies bind to. In the future we can use the information to design new carbohydrate-based vaccines that may prevent disease spread. Thus, in the long-term this research will have wide application to many infectious agents displaying carbohydrates on their surfaces and may potentially help prevent infectious diseases such as HIV.

The elicitation of protective antibodies is a key step in successful vaccination. Bacterial conjugate vaccines elicit protective antibodies specific for the carbohydrate coat of pathogenic bacteria. This, along with the recent discovery of carbohydrate-specific antibodies that potently neutralise many circulating HIV-1 isolates, highlights carbohydrates on pathogens as important, under-researched targets for vaccine design. Very little is known about the molecular rationale of antibody recognition of carbohydrate antigens, and several basic questions remain unanswered: How do carbohydrate-specific antibodies bind with high affinity? How do they discriminate between self and non-self carbohydrates? How does the immune system elicit these types of antibodies during a viral or bacterial infection? These questions will be explored by studying carbohydrate-specific antibodies against HIV-1 and bacteria. The aims of the proposal are 1) to explore the mechanisms by which carbohydrate-specific bnAbs are elicited during HIV infection and 2) to molecularly characterise antibodies elicited against bacterial conjugate vaccines and during bacterial infection. Firstly, I will characterise the binding interactions of germ line versions of carbohydrate-specific HIV bnAbs and isolate mannose-specific antibodies from HIV-infected donors to give insight into the origin of these bnAbs in HIV infected individuals. Secondly, I will characterise the antibodies elicited through immunisation with Streptococcus pneumoniae vaccines PrevnarTM and PneumovaxTM. Antigen-specific B cell sorting will be used to isolate antibodies for subsequent characterisation at the molecular level including x-ray crystallography. The overall goal of this fellowship is to increase our fundamental understanding of the antibody recognition of carbohydrates and to build a scientific foundation for rational design of carbohydrate-based vaccines against HIV-1 and other pathogens displaying carbohydrates.

In addition to the academic beneficiaries described, the proposed research has potential to improve the health and well being of the general public both nationally and internationally. The proposed research has the long-term goal of developing new carbohydrate-based vaccines that will protect against the spread of infectious disease and will therefore benefit all, but particularly infants, the elderly and the immunocompromised.

HIV impacts low-income countries in particular sub-Saharan Africa and although anti-retroviral treatment has helped reduce the death rate these drugs are extremely expensive. An effective HIV vaccine would not only curb the pandemic but also reduce the burden of treatment costs. Therefore, in the long-term, this research potentially has economic benefits too. Although the proposed research focuses on two pathogens, HIV and Streptococcus pneumoniae, there is considerable potential to develop carbohydrate-based vaccines against other glycosylated pathogens e.g. HCV, and fungal pathogens (e.g. Candida, Cryptococcus and Aspergillus).

As the proposed research involves basic science it may be several years before vaccines are developed for subsequent translation to clinical trials. Therefore these beneficiaries may not be reached for some time.