Dissecting the host immune response to bacterial and HIV carbohydrate antigens to guide vaccine design
Lead Research Organisation:
King's College London
Department Name: Immunology Infection and Inflam Diseases
Abstract
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.
Technical Summary
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.
Planned Impact
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.
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.
People |
ORCID iD |
K Doores (Principal Investigator / Fellow) |
Publications
Granger LA
(2021)
Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection Short Pulse Anti-Retroviral Therapy at Seroconversion cohort.
in AIDS (London, England)
Allen JD
(2018)
Harnessing post-translational modifications for next-generation HIV immunogens.
in Biochemical Society transactions
Huettner I
(2022)
Cross-reactivity of glycan-reactive HIV-1 broadly neutralizing antibodies with parasite glycans.
in Cell reports
Behrens AJ
(2016)
Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein.
in Cell reports
Pritchard LK
(2015)
Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers.
in Cell reports
Allen ER
(2018)
A Protective Monoclonal Antibody Targets a Site of Vulnerability on the Surface of Rift Valley Fever Virus.
in Cell reports
Crispin M
(2015)
Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design.
in Current opinion in virology
Rissanen I
(2020)
Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein.
in eLife
Seabright GE
(2019)
Protein and Glycan Mimicry in HIV Vaccine Design.
in Journal of molecular biology
Pritchard LK
(2015)
Glycan Microheterogeneity at the PGT135 Antibody Recognition Site on HIV-1 gp120 Reveals a Molecular Mechanism for Neutralization Resistance.
in Journal of virology
Coss KP
(2016)
HIV-1 Glycan Density Drives the Persistence of the Mannose Patch within an Infected Individual.
in Journal of virology
Pritchard LK
(2015)
Cell- and Protein-Directed Glycosylation of Native Cleaved HIV-1 Envelope.
in Journal of virology
Doores KJ
(2015)
Two classes of broadly neutralizing antibodies within a single lineage directed to the high-mannose patch of HIV envelope.
in Journal of virology
Bitto D
(2015)
Determination of N-linked Glycosylation in Viral Glycoproteins by Negative Ion Mass Spectrometry and Ion Mobility.
in Methods in molecular biology (Clifton, N.J.)
Pritchard LK
(2015)
Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies.
in Nature communications
Zeltina A
(2017)
Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization.
in Proceedings of the National Academy of Sciences of the United States of America
Krumm SA
(2016)
Mechanisms of escape from the PGT128 family of anti-HIV broadly neutralizing antibodies.
in Retrovirology
Hopper JTS
(2017)
The Tetrameric Plant Lectin BanLec Neutralizes HIV through Bidentate Binding to Specific Viral Glycans.
in Structure (London, England : 1993)
Doores KJ
(2015)
The HIV glycan shield as a target for broadly neutralizing antibodies.
in The FEBS journal
Rissanen, Ilona
(2020)
Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein
Description | In2science |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | I hosted 1 student in my lab for 1 week as part of the in2science scheme. |
Year(s) Of Engagement Activity | 2019 |
Description | In2science |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | My lab hosted a sixth-form student for 2 weeks through the in2science programme. This programme aims to expose children from disadvantaged schools to a university and research setting and to equip them in their application to university. |
Year(s) Of Engagement Activity | 2018 |
Description | Injecting Hope event at Science museum |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | With the European AIDS vaccine initiative (EAVI2020), we hosted a table at the Injecting Hope late night event at the Science Museum in London. Our specific activity was called "Quest for an HIV-1 vaccine" and involved discussing with the public how vaccines are developed, why and HIV vaccine is needed and why it is more challenging than a COVID-19 vaccine. |
Year(s) Of Engagement Activity | 2022 |
Description | School visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I spoke to year 12 and 13 students doing biology A-level about my research relating to infection and immunity. They had studied the basics of the topic in their lessons and we discussed how research can aid in vaccine development against infectious diseases. |
Year(s) Of Engagement Activity | 2020 |
Description | School visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I visited a local primary school as part of their science week activities. I did a talk about what it was like to be a scientisit and what we actually do. The children were able to ask questions too. |
Year(s) Of Engagement Activity | 2018 |