In a new study published online in the journal Science on December 5, 2019, researchers reported a major advance in the creation of a successful HIV vaccine that is typically not produced by the host animal. If this is validated, the vaccine thus created could help the host resist viral attack with HIV.
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The scientists first defined the issue: when the body is attacked by HIV, it fails to set up an appropriate response that will neutralize the virus. As a result, they understood that they needed to modify the way the immune system responded so as to establish the right kind of antibody production.
Many studies over a number of years have built the foundation on which the current research operates. They have shown how HIV infection results in the production of antibodies that broadly neutralize several different strains of the virus. They also discovered what then happens to shut down this process so that the virus is free to proliferate.
Some of the factors that cause this undesirable outcome include the misidentification of the unusual broadly neutralizing antibodies (bnAbs) by the body as dangerous, leading to negative feedback that prevents their further production; and the need for a few rare mutations that are required in the process whereby the B cell line (that produces antibodies) switches to a bnAb-producing cell line, but which don't usually happen in the natural physiological immune response.
Broadly neutralizing antibodies
BnAbs are very effective antibodies that become more and more strongly bound to the target virus when the B cell producing them undergoes certain specific mutations and thus produces more mature antibodies. The original B cell is then called the germline cell, and any bnAb it produces does not bind to the HIV envelope antigens.
The rationale that prompted the two studies covered here is that a highly effective vaccine can be produced by targeting the germline B cells using properly designed antigens that first stimulate bnAb-producing B cells, and then selectively enhancing the production of those B cells that show the right mutations to produce mature bnAbs. Such an antigen should be able to bind multiple different bnAb-producing B cells since there is a hugely diverse pool of such cells in humans.
In these studies, the scientists zoomed in on finding HIV antigens that would stimulate B cells capable of bnAb production and then selecting those which developed these rare but essential mutations required for the full breadth of neutralization. Their theory is that a vaccine that binds well to B cells that produce bnAbs, but even better to those B cells which have these rare mutations, would not only kickstart the maturation of bnAb-producing B cells but selectively stimulate those B cells with these essential but rare mutations.
Producing the right antigens
Saunders et al. modified a protein found on HIV. Their changes focused on the viral envelope protein, in the V3 glycan region, that was designed to bind any B cell with this rare mutation.
Using an experimental mouse model that could produce human bnAbs, they showed that they could use this immunogenic viral envelope antigen to encourage a B cell line that expressed the essential mutation that would trigger the process of producing bnAbs.
They repeated the process, this time targeting bnAbs that could bind the CD4 site on the outer envelope of the HIV. This also showed the need for a very rare mutation. After tracing the pathway through which this antibody was produced, the researchers were able to develop a second antigen that could also trigger the production of early bnAbs against it.
They tested this antigen in macaque monkeys and found that it selectively encouraged the development of the necessary genetic changes that would lead to the production of anti-CD4 neutralizing antibodies against the CD4 binding site.
In the second study, Steichen et al. also found that they could bind germline bnAb-producing B cells using HIV envelope trimer-based antigens, providing a screening test. In mice, these antigens stimulated bnAb-producing B cells with the right type of rare mutations.
Using a vaccine that included these antigens, Saunders et al. found that the mice produced a neutralizing antibody with these rare mutations, and which could neutralize multiple strains of HIV-1. They were able to retrace how these mutations induced antibody production via the B cell genetic structure, the initial bnAb structure, and the vaccine-induced antibody structure.
Researcher Frederick Alt says, "Our ability to make mouse models that express human broadly neutralizing antibodies has provided powerful new model systems in which we can iteratively test experimental HIV vaccines."
Both studies thus present an elegant solution that overcomes the innate reluctance of the host immune system to change its genetic makeup to introduce needed mutations that will help generate these powerful antibodies against HIV.
We have identified the mutations we need, which the immune system won't easily make, and can select for them in a vaccine that targets that mutation. We have shown that we can overcome this major roadblock and can select for the right mutational changes in these bnAb precursors when they are starting to get better and better at neutralizing activity."
First study author, Kevin Saunders
Noting that it would take many decades of immunization before these mutations occurred by chance to produce effective antibodies, Saunders et al. say they can now speed up the time to effective protection by engineering a sequence of immunogenic challenges that will each selectively enhance the occurrence of a necessary set of antibody mutations that enhance the function of these immune molecules. More studies are urgently required to find new protective antibodies that they can induce by including the appropriately engineered antigens in a functional vaccine.
Much more work lies ahead, but the experiment has shown how involved the process of inducing bnAbs from an HIV challenge is, and also throws light on possible future applications. For instance, researchers say, "This strategy of selecting specific antibody nucleotides by immunogen design can be applied to other infections for which vaccine development has been difficult."
The whole process hinges on the understanding of how the B cells are regulated in the immune system, and how to make the immune response function in the right way using these B cells.
Moreover, the same logical process could be used to design new cancer immunotherapies and autoimmune treatments. Both of these are also based on switching off certain specific immune responses but preserving the immune system's ability to function normally otherwise. Moreover, the switching off must be very precisely targeted so that other essential body functions are not affected.
Saunders, K.O. et al. (2019). Targeted selection of HIV-specific antibody mutations by engineering B cell maturation. Science. DOI: 10.1126/science.aay7199.
Steichen, J.M. (2019). A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses. Science. DOI: 10.1126/science.aax4380.