By Esther Cooke, PhD
Infection with HIV remains a prominent pandemic. Last year, an estimated 36.7 million people worldwide were living with HIV, two million of which were newly infected. The HIV pandemic most stringently affects low- and middle-income countries, yet doctors in Saskatchewan, Canada are calling, in September 2016, for a state of emergency over rising HIV rates.
Since the mid-20th century, we have seen vaccination regimes harness the spread of gnarly diseases such as measles, polio, tetanus, and small pox, to name but a few. But why is there still no HIV vaccine?
When a pathogen invades a host, the immune system responds by producing antibodies that recognise and bind to a unique set of proteins on the pathogen’s surface, or “envelope”. In this way, the pathogen loses its function and is engulfed by defence cells known as macrophages. Memory B cells, a type of white blood cell, play a pivotal role in mounting a rapid attack upon re-exposure to the infectious agent. The entire process is known as adaptive immunity – a phenomenon which is exploited for vaccine development.
The cornerstone of adaptive immunity is specificity, which can also become its downfall in the face of individualistic intruders, such as HIV. HIV is an evasive target owing to its mutability and highly variable envelope patterns. Memory B cells fail to remember the distinctive, yet equally smug, faces of the HIV particles. This lack of recognition hampers a targeted attack, allowing HIV to nonchalantly dodge bullet after bullet, and maliciously nestle into its host.
For HIV and other diverse viruses, such as influenza, a successful vaccination strategy must elicit a broad immune response. This is no mean feat, but researchers at The Scripps Research Institute (TSRI), La Jolla and their collaborators are getting close.
The team have dubbed their approach to HIV vaccine design a “reductionist” strategy. Central to this strategy are broadly neutralizing antibodies (bnAb), which feature extensive mutations and can combat a wide range of virus strains and subtypes. These antibodies slowly emerge in a small proportion of HIV-infected individuals. The goal is to steer the immune system in a logical fashion, using sequential “booster” vaccinations to build a repertoire of effective bnAbs.
Having already mapped the best antibody mutations for binding to HIV, Professor Dennis Burton and colleagues at TSRI, as well as collaborators at the International AIDS Vaccine Initiative, set out to prime precursor B cells to produce the desired bnAbs. They did this using an immunogen – a foreign entity capable of inducing an immune response – that targets human germline B cells. The results were published September 8, 2016 in the journal Science.
“To evaluate complex immunogens and immunization strategies, we need iteration – that is, a good deal of trial and error. This is not possible in humans, it would take too long,” says Burton. “One answer is to use mice with human antibody systems.”
The immunogen, donated by Professor William Schief of TSRI, was previously tested in transgenic mice with an elevated frequency of bnAb precursor cells. Germline-targeting was easier than would be the case in humans. In their most recent study, the Burton lab experimented in mice with a genetically humanised immune system, developed by Kymab of Cambridge, UK. This proved hugely advantageous, enabling them to study the activation of human B cells in a more robust mouse model. Burton speaks of their success:
“It worked! We could show that the so-called germline-activating immunogen triggered the right sort of antibody response, even though the cells making that kind of response were rare in the mice.”
The precursor B cells represented less than one in 60 million of total B cells in the Kymab mice, yet almost one third of mice exposed to the immunogen produced the desired activation response. This indicates a remarkably high targeting efficiency, and provides incentive to evaluate the technique in humans. Importantly, even better immunisation outcomes are anticipated in humans due to a higher precursor cell frequency. Burton adds that clinical trials of precursor activation will most likely begin late next year. If successful, development of the so-called reductionist vaccination strategy could one day spell serious trouble for HIV, and other tricky targets alike.