Worldwide, 20 percent of children are not completely immunized, which leads to 1.5 million children’s deaths every year due to diseases that can be prevented by vaccination. Around half of the little immunized children received at least one dose of vaccine, but did not complete the vaccination series, while the rest did not receive vaccines at all.
To facilitate that children receive all their vaccines, MIT researchers are working to develop microparticles that can release their useful load weeks or months after being injected. This could lead to vaccines that can be administered only once, with several doses that would be released in different points of time.
In a study that appears today in the magazine Advanced materialsThe researchers showed that they could use these particles to deliver two doses of diphtheria vaccine, one immediately released and the second two weeks later. The mice that received this vaccine generated as many antibodies as mice that received two separate doses two weeks apart.
Researchers now hope to extend these intervals, which could make particles useful for administering children’s vaccines that occur as several doses for a few months, such as the polyomyelitis vaccine.
“The long -term objective of this work is to develop vaccines that make immunization more accessible, especially for children living in areas where it is difficult to reach medical care facilities. This includes rural regions of the United States, as well as in parts of the world in development of the world where the Infrastructure and Medical Institute is limited,” says Ana Jaklenec, principal researcher at the Koch Institute of the MIT for the integrative research of integrative cancer.
Jaklenec and Robert Langer, professor of the David H. Koch Institute at MIT, are the main authors of the study. Linzixuan (Rhoda) Zhang, a graduate student from MIT who recently completed his doctorate in chemical engineering, is the main author of the document.
Autopotent vaccines
In recent years, Jaklenec, Langer and his colleagues have been working on vaccine supply particles made of a polymer called PLGA. In 2018, they demonstrated that they could use this type of particles to deliver two doses of the polyomyelitis vaccine, which were released approximately 25 days apart.
An disadvantage of PLAGA is that as the particles decompose slowly in the body, the immediate environment can become acidic, which can damage the vaccine contained within the particles.
The MIT team is now working on ways to overcome that problem in plga particles and is also exploring alternative materials that would create a less acidic environment. In the new study, led by Zhang, the researchers decided to focus on another type of polymer, known as polynhydride.
“The objective of this work was to advance in the field exploring new strategies to address the key challenges, particularly those related to ph sensitivity and antigen degradation,” says Jaklenec.
Polyhydrides, biodegradable polymers that Langer developed for the administration of drugs more than 40 years ago, are very hydrophobic. This means that as polymers gradually erode inside the body, decomposition products are barely dissolved in water and generate a much less acidic environment.
Polianhydrids generally consist of chains of two different monomers that can be assembled in a large number of possible combinations. For this study, the researchers created a library of 23 polymers, which differed from each other depending on the chemical structures of monomer construction blocks and the relationship of the two monomers that entered the final product.
The researchers evaluated these polymers based on their ability to resist temperatures of at least 104 degrees Fahrenheit (40 degrees Celsius, or slightly above body temperature) and if they could remain stable during the entire process required to form them in microparticles.
To make the particles, the researchers developed a process called printed assembly of polymer or seal layers. First, they use silicon molds to form particles in the form of a cup that can be filled with the vaccine antigen. Then, a lid made of the same polymer is applied and sealed with heat. The polymers that proved to be too fragile or did not completely sealed were eliminated from the pool, leaving six main candidates.
The researchers used these polymers to design particles that would administer diphtheria vaccines two weeks after injection, and gave them to mice along with the vaccine that was released immediately. Four weeks after the initial injection, these mice showed comparable levels of antibodies against mice that received two doses two weeks apart.
Extended release
As part of their study, the researchers also developed an automatic learning model to help explore the factors that determine how long it takes the particles to degrade once in the body. These factors include the type of monomers that enter the material, the relationship of the monomers, the molecular weight of the polymer and the load capacity or the amount of vaccine can enter the particle.
Using this model, the researchers could quickly evaluate almost 500 possible particles and predict their release time. They tested several of these particles in controlled tampons and showed that the model’s predictions were precise.
In future work, this model could also help researchers develop materials that release their payload after longer intervals, months or even years. This could make them useful to deliver many children’s vaccines, which require multiple doses for several years.
“If we want to extend this to longer points of time, say more than a month or even more, we definitely have some ways to do this, such as increasing the molecular weight or hydrophobicity of the polymer. We can also potentially make some reticulants. That is more than changes to the chemistry of the polymer to reduce the speed of the liberation kinetics or to extend the retention time of the particle,” says Zhang.
Researchers now hope to explore the use of these delivery particles for other types of vaccines. The particles could also be useful to administer other types of medications that are sensitive to acidity and that should be administered in multiple doses, they say.
“This technology has broad potential for unique injection vaccines, but it could also be adapted to administer small molecules or other biological products that require durability or multiple doses. In addition, you can accommodate medications with pH sensibilities,” says Jaklenec.
The investigation was financed, in part, by the subsidy of the support of the Koch Institute (CORE) of the National Cancer Institute.