Antibodies interfere with our memories of malaria
Antibodies interfere with our memories of malaria
Contributed by Jeremy F Brooks PhD
Vaccines are on everyone’s mind in 2020. We are fortunate that initial testing of COVID-19 vaccines has yielded encouraging outcomes. This has not been the case for malaria vaccines, for which scientists worldwide have also spent considerable effort on developing. For reasons that have eluded us, our best malaria vaccines are inefficient. I previously wrote about how the antibody response to malaria infection is atypical. Here, I explore new research that explains how these antibody responses interfere with long-term protection from malaria parasites.
A vaccine for malaria is a global public health goal. To our credit, scientists have had remarkable success with vaccines against many other pathogens, including hepatitis B and measles. Benefiting from these vaccines relies on them eliciting high levels of neutralizing antibodies that circulate in the blood for our entire lifespan. Additionally, some immune cells are also trained following immunization to remember these pathogens; the generation and maintenance of memory B cells is critical for long-term protective immunity following vaccination. Engaging these memory B cells when a pathogen is re-encountered is critical to boosting protective antibody levels.
If we understand how to generate an immune response and the features that are required for long-term protection, why have we not succeeded in the case of malaria? Our most advanced malaria vaccine – RTS,S – actually generates a very robust immune response. The problem lies with the poor durability of this response. Booster immunizations, a classical approach to enhance antibody levels and therefore improve protection, have failed to do just that. While this has suggested to scientists over the last decade that there was a problem with the vaccine engaging memory B cells, the exact reasons for this have been unexplained.
The Cockburn laboratory at the Australian National University have provided new important insights to this problem in the journal Cell Host and Microbe.
They start out by demonstrating in humans that a new malaria vaccine – as part of a current clinical trial – could generate a good initial immune response, but that it could not be boosted after a third vaccine shot was injected. To some extent, these findings were expected and to dissect the biology further, the researchers take advantage of a creative mouse model. B cells from these mice have been transgenically engineered to recognise malaria pathogens and so can be used to track the immune response to infection in-depth and in ways we cannot in humans.
Using these tools, we learn that memory B cells indeed cannot be reliably engaged by booster vaccination for malaria. A series of elegant experiments rule out that it is an intrinsic defect to these memory B cells – in fact, they are completely functional if they are transferred to a host that has not previously been infected with malaria. Rather, there is a factor present in the serum from malaria-infected individuals that appears to suppress the memory B cells. Unfortunately, this turns out to be the very antibodies that are made to protect against infection.
The researchers point out that this effect is possible even when anti-malaria antibodies are very low in abundance. This is a major challenge, because if the threshold of antibodies that can impair memory B cells is lower than the threshold of antibodies required for malaria protection, then a vaccine like this may never actually offer sterilizing immunity to malaria.
However, it cannot be all bad. There is likely a biological explanation for why this would occur – indeed, it is at a fitness cost to the host if memory cells cannot be engaged. So, we ask is there is an advantage to such a process?
As it turns out, there is. Antibodies that are produced early in the response to vaccination shield part of the malaria pathogen so that B cells recognising other parts also get a fair chance to contribute to the immune response. This “diversifies” the immune response against the pathogen, which gives the host a better chance to resist infection if the pathogen mutates slightly. I previously wrote about this concept during a flu infection; the immune system has fail-safe mechanisms that allow it to broadly target pathogens rather than focus on a limited region.
Not only does this new work reveal why current malaria vaccine strategies are sub-optimal, but it also provides exceptional detail on the cellular and serological dynamics of the immune response to malaria infection. These fundamental insights are what helps us build better vaccines.
Dr Jeremy Brooks is a postdoctoral fellow in the Zikherman laboratory at UCSF. Jeremy’s work focuses on antibodies and the immune cells that produce them. Correspondence can be addressed to jeremy.brooks@ucsf.edu
