The New Technology of Self-Boosting Vaccines

The most common vaccine known for its requirement of boosters (multiple doses) is the flu shot. This is due to the vaccine's make-up: killed version of the germ. Because inactivated vaccines don't provide enough immunity, several doses are needed to get ongoing immunity.

Globally, only 20% of children are not fully immunized due to receiving only one vaccine dose and not completing the vaccination series, leading to deaths that may have been prevented by vaccines. To make it easier to gain immunity, MIT researchers worked on developing microparticles that could release doses months after an initial injection.

The study, Polyanhydride-Based Microparticles for Programmable Pulsatile Release of Diphtheria Toxoid (DT) for Single-Injection Self-Boosting Vaccines, focused on delivering doses of the diphtheria vaccine (diphtheria is a contagious bacterial infection).

Initial Hurdles

Zhang et. al started off with the goal to make a vaccine that mimics multiple doses. The first obstacle was a sufficient system. Current existing systems developed to create self-boosting vaccines includes synthetic polymers (offers controlled release) and continuous release kinetics (the most used of the two). However, continuous release kinetics is not optimal for several reasons.

• The immune system benefits from spaced out antigen exposure

• Continuous release may not effectively replicate the natural process of infection (infection, then periods of rest)

Therefore, pulsatile release kinetics (delivering doses at predetermined times), is ideal because it mimics regular vaccination schedules.

Another big hurdle was changing the reliance on traditional methods that use organic solvents such as dichloromethane. Organic solvents pose concerns due to encapsulation methods, safety concerns, and acidic microenvironment.

1. Encapsulation methods: exposes antigens when making the vaccine to solvents, which can change the shape of the antigens, thus making the vaccine essentially useless

2. Safety concerns: residual solvents could pose health risks to the patient

3. Acidic microenvironment: widely used polymers (PLGA, which we won't go in depth in), degrades into acidic byproducts, which can negatively affect the effectiveness of antigens

As a result, previous researchers developed solvent-free fabrication techniques (fillable core-shell microparticles) that aim precise doses with controlled release.

The Methods

Zhang et. al, to address limitations, synthesized new polyanhydrides. Polyanhydrides, a type of degradable polymers, can release vaccines in waves, thus making it a much better fit when creating single-injection vaccines. Already used in approved medical products, such as Gliadel, a biodegradable disc that is used in brain tumor treatments, polyanhydrides is well-studied.

Although a degradable polymer, polyanhydrides can achieve surface erosion by tuning monomer compositions. Surface erosion refers to the gradual and uniform erosion of the external material of the polymer, which occurs because of the monomer composition - basically, the building blocks of the polymers.

The gradual and uniform erosion of the polymer protects the core, where the antigens are placed, allowing protection from water for a significant amount of time and only during the preset release time. By maintaining a dry core and stopping water penetration into the core, potential antigen shape changes can be prevented. Therefore, when antigens are released, they are able to effectively provide immunity in the human body.

Additionally, DT (Diphtheria toxoid) was the model due to its high thermal stability (does not break down in high temperatures) and sensitivity to acidic conditions, where it quickly loses activity. DT allows researchers to demonstrate the polymer's capability to protect very acid-sensitive antigens. Furthermore, the vaccine is very stable at body temperature and therefore can be delivered effectively.

Steps:

1. Vaccine is injected, antigen's release is triggered by polymer degradation and is released according to preset times

Figure 1. Design and material selection for polyanhydride core-shell MPs

The fabrication method Zhang et. al utilized was creating fillable shells that had layers. When the single-injection vaccine is given, the formula has both the initial dose in its regular form and its polymer protected second dose.

Figure 2. Microscopic characterization of core-shell MPs

Six different polyanhydride compositions of core-shell MPs were created. Three excipients (a substance that acts as a vehicle for a drug, thus the new engineered polyanhydrides) were chosen: trehalose, BSA, and histidine. These were tested both individually and collectively.

1. Trehalose - acts as a protective agent to shield cells from environmental stressors (which will aid in protecting antigens)

2. BSA - Bovine Serum Albumin; known for its stability, acts as a carrier protein that transports molecules and stabilizes enzymes (stability will protect antigens and will work well to carry the antigens into cells)

3. Histidine - vital for growth and repair (pH sensitive so can be easily manipulated to release antigens and has good stability of core)

Results

When trehalose was used as a sole excipient, there was noticeably no antigen successfully released, deeming it insufficient. On the other hand, BSA and histidine each saw 2.2% and 21.8% release of the antigen (histidine is therefore much more better suited for the task). Furthermore, the most stability was seen when the three excipients were combined: 89.7% of antigen release was seen.

Release of antigens were recorded after one week of incubation. Incubation is the process of cultivating cells (in other cases, it can be bacteria, eggs, etc.) in a controlled environment. This is done through controlling temperature, humidity, and composition of the air. However, in a rare case, in histidine only MPs, active antigens were being released for about 2 weeks.

In conclusion, there is much hope for a future for single-injection, self-boosting vaccines. The results show the existence of certain materials that will allow antigens to be protected before being released into the body as a "booster."

Remaining final results will be in the next part!