Vaccine development remains largely trial and error- resulting in costly production and a low success rate. However, Wei Cheng, researcher at the Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, has proposed a theory that can reduce years of vaccine development and lead to more successful vaccines.
“A major hurdle in vaccine development is the lack of general principles that can be applied in the strategic decision and the formulation of a vaccine. The development of a successful vaccine remains largely empirical in nature. Even though the vaccines are available, in many cases, the molecular basis that underlies the successful immune response is not clear,” said Cheng.
In the study published in the Journal of Pharmaceutical Sciences, the Cheng team compared the molecular features of over a dozen successful vaccines licensed by the FDA and discovered a commonality among them: a display of a relatively high density of viral proteins on the surface of the vaccine carrier. These viral proteins activate neutralizing antibodies, which in turn target viral proteins offering immunity from infection in vaccinated subjects.
At the molecular level, there are two potential mechanisms that can explain why a high density of viral proteins on the surface of the vaccine carrier leads to immunity. The first is that a high density of viral proteins facilitates the bivalent binding of a major class of antibodies in the body, called IgG. An IgG antibody contains two identical arms and viral proteins bind to the tip of each arm. When there is a low density of viral proteins on the surface of the vaccine carrier, both arms of the IgG antibody may fail to bind to viral proteins leading to an ineffective neutralizing antibody response. The second mechanism is that a high density of viral proteins facilitates B-cell activation. B-cells play a major role in the humoral immune response by making antibodies against viral proteins. Cheng believes that a threshold number of B-cell receptors need to interact with viral proteins in order for B-cell activation to occur. Cheng also believes that the size of the vaccine carrier plays a role in B-cell activation. If a vaccine carrier is small with a low density of viral proteins, it is likely that there will be more interaction with B-cell receptors, leading to activation. Alternatively, a large vaccine carrier with a low density of viral proteins would likely lead to the least effective activation of B-cells. Cheng concluded that the most effective B-cell activators would be small vaccine carriers with a high density of viral proteins.
According to Cheng, if vaccines were formulated with a focus toward optimizing the density of surface proteins on the carrier, it could shorten vaccine production time and lead to more successful vaccines.
“This perspective may provide a clear route for the development and formulation of antibody-based vaccines with higher probability of success. For a new vaccine, the probability of success is only 6 percent. It’s very important to have something that can be used as a principal to guide this strategic decisions and also the formulation,” said Cheng, adding that his theory of the relationship between protein density and vaccine success has been brewing for some time. In 2014, the team published a paper describing a new optical technique they developed which allowed them to quantify viral proteins on HIV particles. They found that viral protein density determined HIV virulence and protein-rich HIV particles were more infectious than others.
The results of rVSV-ZEBOV, an experimental vaccine against the Ebola virus disease, was a good test of Cheng’s theory. The study, published in the Lancet, reported that 2,119 participants received immediate vaccination and 2,041 participants received vaccination delayed by twenty-one days. In the immediate vaccination group, there were no cases of the Ebola virus disease ten or more days following vaccination. In the group with vaccination delayed by twenty-one days, there were sixteen cases of the Ebola virus disease. Researchers concluded that the rVSV-ZEBOV experimental vaccine was 100 percent effective against the Ebola virus disease. Cheng added that the rVSV-ZEBOV experimental vaccine also had a high density of viral proteins- the same feature Cheng’s lab found in successful vaccines. “The Ebola outbreak was a good test of my theory,” said Cheng. “I was indeed very excited when I saw the patient outcomes reported for Ebola, which is consistent with my theory.”
There are other factors besides high density of viral proteins that contributes to a successful vaccine including dosage and vaccination schedule. Cheng believes that in the short term, retroactive studies can be done on vaccines that are currently in the preclinical and clinical trial stages to take his findings into account.
