In a new study, researchers from the Scripps Research Institute in the United States proposed a faster way to analyze the results of experimental vaccines against HIV and other pathogens. Their new approach allows scientists to quickly assess the full spectrum of antibodies produced by individuals in response to a pathogen or vaccine and determine if these antibodies are likely to be effective against the pathogen. The results of the study were published in Immunology, entitled “Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization”. The author of the paper was Dr. Lars Hangartner and Dr. Andrew Ward from the Scripps Research Institute.
Hangartner said, “We are now able to observe antibody responses in nearly real time,” Ward added. “This can be applied to any pathogen.”
When a pathogen attacks, your immune system will gather a large group of antibodies to fight back. Some of these antibodies fail, but some may be close to defeating the pathogen’s defenses. Over time, these best antibodies have evolved to target vulnerable sites of pathogens. If all goes well, the antibodies will target these epitopes, neutralize the invaders and provide lifelong immunity.
Vaccines work by inducing the body to produce neutralizing antibodies against future invaders. Testing a vaccine is often a lengthy process: after a primary immunization, a series of booster vaccinations are performed over weeks or months. The time it takes to analyze the test data means that scientists often don’t see if the vaccine is effective until the end of the experiment, making it particularly difficult to adjust treatment strategies in the face of emerging diseases.
Through this new study, scientists finally have a way to map antibody evolution maps in nearly real time. This new technology builds on the immunological breakthrough which led by the Scripps Research Institute and an imaging technique called electron microscopy. The use of this imaging technique reveals the structure of antibodies that bind to target pathogens such as HIV.
These researchers used blood samples of rabbit collected at different stages of an HIV vaccine trial. They purified these samples and degraded the purified molecules until they were able to extract antibody fragments. They then mixed these antibody fragments with their targets (ie, viral proteins) and imaged them under an electron microscope to reveal how the immune system initiated an attack on the pathogen.
Dr. Matteo Bianchi, co-author of the paper and a former researcher at the Scripps Research Institute (now working at the Institute of Medical Virology at the University of Zurich, Switzerland), said, “After fine-tuning the biochemical properties of immune complexes formed by HIV Env trimers and antibody fragments, we were able to establish a very reliable method that allowed for semi-quantitative electron microscopy analysis.”
This new approach is based on a relatively low-tech method called negative stain imaging, which helps these researchers find promising antibodies or, more commonly, finds less attractive antibodies.
Finally, these researchers were able to quickly discover whether a vaccine is pushing the immune system along the right path. In the case where a vaccine does not work, this method can provide information about how to improve the vaccine.
Hannah Turner, the co-author of the paper and research assistant at Ward Labs, said, “You can change the direction of research based on the results of this method. We have never taken pictures of our antibodies like this before, which gives us a more complete understanding of what happens and how we can influence the vaccination process.”
Although the images obtained are not high-resolution, these researchers are happy to report that this level of analysis—in just a few days—may become a routine test worldwide. Ward said, “Most research institutes have at least the technology and resources to conduct this level of analysis.”
To look at these antibodies more closely, Ward used high-tech cryo-electron microscopy to obtain high-resolution 3D images of these antibodies when combined with their viral targets. These detailed images reveal more details that may help scientists improve experimental HIV vaccines in the future.
The researchers say their faster approach may open the door to personalized vaccine design. For example, the study included “highly reactive” rabbits that produced many effective antibodies and “low reactivity” rabbits that produced many weaker antibodies. Looking ahead, people may use this new method in human vaccines or therapeutic trials to quickly distinguish high responders from low responders in the early stages, thus finding effective treatments and vaccines for patients and their physicians that provide group immunity, and save critical time.
Matteo Bianchi, Hannah L. Turner, Bartek Nogal et al. Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization. Immunity, Published Online: 07 August 2018, doi:10.1016/j.immuni.2018.07.009.