Better for Everyone: Subunit Vaccines of the Future

Schematic of the HIV Viron Showing the gp120/gp140 Type I Fusion

Glycoprotein Assesmbly

Medicines are only useful to the extent that they can reach at-risk populations. Unfortunately, when it comes to some of the world's most deadly viruses, sending effective vaccines into the developing world has proved difficult. Luckily, a new generation of vaccines, the subunit vaccines, promises improved access for men, women, and children living beyond the reach of the refrigeration "cold-chain" that has traditionally limited distribution. That subunit vaccines are also safer and less expensive than other varieties has made them the focus of intense research efforts that are beginning to bear fruit. Recent work from the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases published in the journal Nature, for example, describes a strategy that could be used to bring subunit vaccines for diseases like HIV, influenza and respiratory syncytial virus into reach.  

Vaccines work by offering the body a "sneak peak" at pathogens-disease causing microorganism-that it might later encounter in a less controlled setting. This is true whether the goal is provide protection against a viral or a bacterial species. Immunization allows the immune system to build the infrastructure needed to recognize and neutralize the relevant pathogen should you becomes infected. The recognition process follows from the ways that the surfaces of foreign microorganisms differ from the surfaces of an individual's own anatomical structures. Therefore, vaccines need only expose the body to the surface structures of pathogens, not their entire construction. This is the logic behind subunit vaccines: identify and vaccinate patients with key elements of pathogen surfaces that the immune system can rely on to recognize those foreign substances. The prominent structural elements here are typically proteins, an important class of biomolecules. Like anything else in science, this if often easier said then done.

The keys to crafting an effective subunit vaccine are twofold. First, researchers must identify a structure or group of structures on the pathogen surface that are unique among other microorganisms but common to all or many of the strains of the target microorganism. These structures must be found to act as immunogens that lead to immune responses that are both strong and protective against various strains. Second, researchers must find a way to stabilize the identified structures, which in their native environments on bacterial or viral surfaces might be supported by interactions with other structures. It is this stabilization that the VRC's findings might simplify in the future. By fusing viral surface proteins to rigid assemblies of the protein ferritin, VRC scientists discovered a method for stabilizing the surface structures that that may advance HIV, RSV, and influenza vaccine efforts. No vaccine for HIV or RSV is availible; a subunit vaccine for influenza could protect against more stains than do currently available formulations.

What do HIV, RSV and influenza have in common such that their vaccine efforts are linked? All three viruses display on their surfaces protein structures known as type I fusion glycoproteins (TIFGs). In all three cases, TIFGs occur in groups of three that are arranged as tripods. It is thought that these tripods, formally known as trimers, will acts as effective immunogens. What has been proven difficult, however, is holding groups of TIFGs together as trimers where they are not connected to entire viruses. Work at the VRC has shown that it is possible to attach TIFGs to assemblies of the bacterial protein ferritin in a way that will stabilize them in trimeric configurations. Twenty-four ferritin molecules come together to form a ball-shaped nanoparticle whose surface hosts eight locations that can each connect to one TIFG trimer. When scientists express (create) proteins for use in subunit vaccines they do so artificially and in a manner completely separate from the organism in which the protein naturally occurs. This being the case, a subunit vaccine that combines bacterial ferritin assemblies with TIFGs isolated from HIV, RSV or influenza has the ability to infect an individual with no bacterial or viral disease. 

Whether efforts to create clinically useful ferritin nanoparticle vaccines for viruses that host TIFGs on their surfaces will be successful has yet to be seen. In their Nature article, authors from the VRC present a nanoparticle vaccine that offers strong protection against various influenza strains. Their construct, however, has yet to be tested in humans or even in large pools of animals. While the subunit approach has appeal as a way to create effective, safe, inexpensive and distributable vaccines, the human body is a complex machine whose reaction to a foreign substance is difficult to predict. Whether new ferritin nanoparticle vaccines are safe for widespread use should become clear during the years-long process of clinical testing that must precede marketing. 

NIH Vaccine Info Link: http://www.vaccines.gov/more_info/types/#subunit

See: Kanekiyo M, Wei CJ, Yassine HM, McTammney PM, Boyington JC, Whittle JRR, Rao SS, Kong WP, Wang L, Nabel GJ. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. 2013. Nature. 499: 102-106.

Image Credit: NIAID. HIV Viron Structure. 2010. Digital Image. Flickr. Yahoo! Inc. Web. 6 March 2015. < https://www.flickr.com/photos/niaid/5080768345/in/photolist-bGyEX-8Dzz22-c1h9K9-9yAr3e-hiCNVA-896Don-8GSyC4-8TUEm5-aRwNc4-pbcQYr-7fuCyB-8fYoYE-fAfySA-8CWtKR-8CJbyd-6TzA7P-7S5A18-ewXXK1-8JYgqe-ewXXGW-8DPVSb-3bEcxA-aN9ZBR-97GD84-aN9Zp8-88XcAr-bo55zH-8wNGmZ-7uFUDn-4mkiXQ-77VqAw-9vmf4X-9ApBzB-9bV8Dq-4pycVt-3WU1bF-624rq-8CJbxY-fomL-8CGVWs-8DNhY8-9dHfxP-8mNuXa-8CDgXZ-8CJbxJ-aRZt4t-afRKUN-8e28LT-aXqSAc-i3m2Ak>.