News Excerpt:
Researchers at the Scripps Research Institute and the Massachusetts Institute of Technology have unearthed two promising vaccine candidates that could engage B-cells to make broadly neutralising antibodies to attack HIV.
Background:
- In early 1981, Michael Gottlieb, an assistant professor at the University of California Los Angeles Medical Centre, with his students was investigating a rare infection called pneumocystis pneumonia in a few patients.
- Dr. Gottlieb published a paper detailing these five cases in a small American journal called Morbidity and Mortality Weekly. At the time, Dr. Gottlieb had no idea his paper was about to change the field of immunology forever.
- That paper was the first report of acquired immunodeficiency syndrome (AIDS).
Challenges in developing AIDS Vaccine:
- Today, nearly half a century after Dr. Gottleib’s landmark publication in 1981 that first pointed out the presence of this rare autoimmune disease, AIDS still has no vaccine or cure.
- This anomaly in humanity’s otherwise remarkable track record in tackling major infectious diseases is a result of several factors.
- The primary factor is the incredibly error-prone replication process of the human immunodeficiency virus (HIV), which causes AIDS, resulting in multiple variants of the virus circulating.
- The sheer number of all the different strains circulating in the world is in fact the biggest challenge to an HIV vaccine today.
- HIV has more variants circulating in a single patient at any given point of time than influenza cumulatively generates in one year in all influenza patients around the world combined.
- Influenza is considered the second-best virus in terms of genetic variation, highlighting the exceptional variability of HIV.
Role for B-cells and Vaccines
- When the immune system encounters a virus, one of its responses is to produce antibodies highly specific to proteins on the surface of the virus (virions).
- Each antibody is unique to a small piece (fragment) of a given protein, and the immune system can generate antibodies against any fragment of any protein.
- The immune system generates these antibodies through a pool of specialized cells called B-cells,
- Each B-cell produces an antibody unique to one protein fragment.
- When a B-cell encounters a similar protein fragment on a virus or bacteria, it refines the antibody until it binds perfectly to the target, rendering the virus incapable of further infection.
- The body retains some of these specific antibody-producing cells in case of a future infection by the same virus.
- A vaccine aims to generate these antibodies prior to viral infection so that when the virus enters the body, the antibodies can neutralize the virus and prevent infection.
- The vaccine provides the immune system with a head-start by allowing the body to make antibodies without an actual infection with the real virus.
bNAb, a sliver of hope
- When multiple variants of the same virus exist, generating antibodies against all the different variants simultaneously becomes very challenging.
- For most viruses, the immune system ultimately catches up, but against HIV, it doesn't due to the sheer volume of different circulating variants, overwhelming the immune system's ability to generate new antibodies.
- By the time the immune system makes antibodies against a few HIV strains, the virus will have produced hundreds more variants.
- In the early 1990s, scientists noticed that a small subset of HIV-infected individuals produced a new antibody called broadly neutralizing antibodies (bNAbs), capable of neutralizing many circulating viral strains.
- bNAbs work by targeting areas of the viral proteins that the virus cannot afford to change, as doing so would make it lose infectivity.
- Some of these bNAbs can effectively neutralize more than 90% of circulating HIV strains.
- However, the catch is that a body usually takes years to make bNAbs, and by then, the virus has already evolved to escape them.
Light at the tunnel’s end
- The main challenge has been to make the immune system produce bNAbs in large numbers in response to a vaccine. The route to doing this, called germline targeting, has three steps.
- In the first step, those B-cells that can mature into cells that can produce bNAb are identified and engaged to increase their population and prepare them for the second-step, where a booster dose will guide these cells into generating stronger bNAbs against HIV. The final step is to refine these bNAbs such that they can neutralise a wide range of HIV strains.
- After years of painstaking failures, researchers have established a possible roadmap for the first two steps of germline targeting for two groups of bNAbs.
- Four papers recently published in Science journals outlined two promising nanoparticle-based vaccine candidates: N332-GT5 and eOD-GT8.
- Teams from the Scripps Research Institute and MIT demonstrated that novel vaccines can engage B-cells to produce two classes of bNAbs.
- The teams demonstrated the efficacy of their vaccine candidates (N332-GT5 and eOD-GT8) in two forms: protein and mRNA.
- The mRNA form of the vaccine is important because mRNA vaccines are easy to develop and produce.
- In both the protein and mRNA forms, the antibodies generated in response to the vaccine can bind to the HIV proteins in a manner similar to established broadly neutralizing antibodies (bNAbs).
- The candidate vaccines are currently being evaluated in a phase-1 clinical trial to assess their performance in humans.
- For the second step of germline targeting, the research groups have reported a possible candidate called g28v2, which is a protein fragment.
- The g28v2 protein fragment appears to be able to guide the cells into making bNAbs.
- Further research is ongoing to evaluate the properties of the g28v2 protein fragment in guiding the production of bNAbs.
Conclusion:
While these four papers do imply progress in developing a B-cell based vaccine for HIV after decades of frustrating wait, we must refrain from celebrating too early. Results from mouse and macaque models don’t always translate to positive results in the human system. The strategies reported by these publications do have enormous potential for vaccine development against other RNA viruses such as influenza, various coronaviruses, and hepatitis C but our past failures have also taught us to remain sceptical with HIV until the very end.
