Self-Boosting Vaccines Are Near At Hand
By Deborah Borfitz
August 24, 2022 | Researchers at the Massachusetts Institute of Technology (MIT) have been working on “self-boosting” vaccines for a decade now, motivated by the crisis of under-immunized children in some of the poorer countries of the world with no healthcare infrastructure. Thanks to the COVID-19 pandemic, curiosity about the underlying platform has piqued in First World nations where vaccination boosters now have personal everyday relevance, says Ana Jaklenec, research scientist at MIT’s Koch Institute for Integrative Cancer Research.
If a self-boosting COVID-19 vaccine hit the market, it would certainly improve patient compliance and potentially minimize the number of viral variants by doing away with the inconvenience of having to get a second, third, or even fourth shot to maintain immunity, she says. As it is, fewer and fewer people are getting boosters for reasons that also include divided beliefs regarding need and effectiveness.
The key enabler of self-boosting vaccines are hollow microparticles, first described in a 2017 article in Science (DOI: 10.1126/science.aaf7447), which are fabricated from a biocompatible polymer called PLGA used to make resorbable sutures, and a host of other therapeutic devices approved by the U.S. Food and Drug Administration. In a paper newly published in Science Advances (DOI: 10.1126/sciadv.abn5315), the MIT team explored ways to help stabilize drugs and vaccines on the platform and optimize their kinetics.
The injectable, cup-shaped particles and their lids can be custom-built to any desired shape and size, and the staggered release of the contents—be it a drug or a vaccine—are controlled by the composition of the polymer and the chemical groups attached to the ends of it, Jaklenec explains. An automated dispensing system fills the cups, and the lid is fused on with pressure and a small amount of heat, a technique aptly termed SEAL (StampEd Assembly of polymer Layers).
In terms of flexibility, “the sky is the limit” on particle configuration, she says. But practically speaking, “you want to go as small as possible because that will be the easiest to inject without losing the ability to fill it and close it.”
Other types of self-boosting vaccines have been proposed, she adds, but “our platform is unique in that it does not involve work on the vaccine itself.”
Breaking The Bond
Polymers are long-chained molecules that might be thought of like long hair or spaghetti that gets tangled up, she says, and the PLGA variety is comprised of lactic acid and glycolic acid. Water eventually breaks the bond between those two building blocks. When enough of these polymers have broken down, the lid suddenly becomes porous and breaks apart, which is key to the pulsatile release of the contents.
Adjusting the lactic acid level up or down will, respectively, lengthen or shorten the time it takes for the water to cleave that bond and degrade the material, says Jaklenec. Other determinants of the release time point in the largely aqueous human body include the length of the chain, with longer chains having more bonds for water molecules to break. Each chain can also have a different end group which, if more hydrophobic, will take longer to degrade.
The main limitation to broad application of the drug/vaccine delivery approach would be dosing, Jaklenec continues. “Whatever your normal dose is, you are also going to have the added mass of the polymer,” which could be tricky for anything requiring a “super-huge” dose.
Currently, researchers are injecting around 20 particle doses into a small animal model, she says. Human dosing for three different vaccines and three different boosters may require 200 or more particles depending on the dose, each smaller than a grain of sand.
The core-shell microparticles are nonetheless a true platform, she says, which can accommodate the mixing and matching of several vaccines together with their boosters as well as cancer drugs, hormone therapy, and biologics.
The tiny injectable cups have been successfully used to deliver a STING agonist for cancer immunotherapy in some mouse tumor models, as shared in a 2020 article in Science Translational Medicine (DOI: 10.1126/scitranslmed.aaz6606). The STING agonist-loaded microparticles were also administered during surgical resection to improve response to immune checkpoint blockade therapy and decrease the tumor recurrence rate in mouse models of melanoma.
Two years earlier, in a study that published in PNAS (DOI: 10.1073/pnas.1720970115), a similar PLGA formulation was used for timed delivery of an inactivated polio vaccine with a single administration. Two bursts of the vaccine were released one month apart, mimicking a typical vaccination schedule in the developing world, and just one injection of the controlled-release formulation had a similar or better neutralizing response in rats than multiple injections of liquid vaccine.
In fact, the bulk of research on the platform has been funded by the Bill and Melinda Gates Foundation, whose name is on patents held by MIT related to this work. “The idea of how to do this came out of a discussion we had on how we could realize the concept of self-boosting vaccines.” Millions of children die each year in the developing world because they don’t get the full course of a needed vaccine.
The MIT team is now focused primarily on addressing the instability risk of the cargo, says Jaklenec. While it’s possible to make a particle that can stay in the body for two years or longer, keeping a drug or vaccine alive or active for that long is the challenge.
Different additives can go into the cup, or the wall of the particles themselves can be altered, to help stabilize the vaccine that’s inside, she says. The twin objectives are to prevent a drop in pH from affecting the vaccine and immobilizing the vaccine to prevent it from aggregating with itself inside the particle over time, rendering it inactive.
Path To Market
Jaklenec has microfabricated the platform out of other materials where the goal was triggered release when the pH level outside the microparticles reached a very low or high level, such as a drug in the stomach. Her preference for working with PLGA, especially for the vaccine applications, is related to its longtime use in the clinic and strong record of safety in all age groups, including infants, she says.
The self-boosting polio vaccine continues to be tested in animal models. Excluding the newer mRNA varieties, polio is one of the most unstable of vaccines, says Jaklenec. Temperature is the big challenge here, since the polio vaccine—which generally requires refrigeration—would need to be stored in the body at 37 degrees Celsius for many months.
Prototypes developed for three different versions of the polio vaccine have shown that one injection with the microparticles elicits the same neutralizing immune response in rats as giving them multiple shots, she reports. “Now that work is in non-human primates, and we hope soon to be able to do a small human trial.”
Clinical trials could start within the next two years, but how soon a self-boosting vaccine hits the market will be a function of resources, says Jaklenec. “If you had asked me a few years ago I would have said it is going to be at least 10 years, but now I am optimistic it is going to be a lot faster than that.”