Technological Advancements Clear Path to HIV Vaccine

Recent research has resulted in countless HIV candidate vaccines, but few have translated to successful clinical trials. A significant hurdle that scientists have had to overcome is the technical difficulty of manufacturing vaccines due to the envelope proteins of HIV.

However, a new investigational method may be able to improve HIV vaccine production, according to a presentation at the Keystone Symposia Global Health Series. This approach seeks to solve the significant technical issues facing the creation of an HIV vaccine.

"Dozens of interesting vaccine candidates have been described, but most have not been tested in humans because it has not previously been possible to manufacture them affordably and in a timely fashion," researcher Phil Berman, PhD, said in a press release. "The technology we developed should break the logjam in HIV vaccine development, because it tremendously shortens the time, improves the yield, and lowers the cost."

The team of researchers used robotics to streamline the process of producing stable cell lines that are required to make the proteins for a vaccine, according to the session.

This method also drastically increases the protein production of the cell lines, so much so that it can reduce the size of the bioreactor needed for the vaccine from 200- to 10,000-liter vessels to 50- or 100-liter vessels, which leads to significant savings, Dr Berman said during the session.

Additionally, the researchers were able to create cell lines that produce the glycans needed for optimal immune response.

"The carbohydrates attached to the protein are really important, something no one realized until recently," Dr Berman said. "The conventional way of making these envelope protein vaccines incorporated the wrong kind of carbohydrates. We now know that destroyed many of the important antigenic sites recognized by protective antibodies."

Currently, Chinese hamster ovary (CHO) cells are the standard for producing complex recombinant proteins for therapeutics, including HIV vaccines. The gene for the target protein is transferred into CHO cells and tens of thousands of the cells are screened to discover cells that produce large amounts of the protein. The highest producing cell lines are then grown in large batches and the resulting proteins are isolated and purified, according to the session.

The novel robotic method reducing the time needed to produce stable cell lines to a maximum of 3 months compared with 18 to 24 months with traditional methods. The yields also increased by a factor of 100 to 200, Dr Berman reported.

Previously, Dr Berman worked on the AIDSVAX vaccine, which was a component of an investigational regimen used in a clinical trial. This regimen was only 31% effective in mitigating HIV infections, according to the session.

The trial results suggested that protection against HIV was linked to antibodies for gp120, a segment of the HIV envelope protein. However, other studies showed that the most potent antibodies recognize the glycans attached to gp120, according to the session.

"We realized that the original AIDSVAX vaccine had the completely wrong type of carbohydrate, and that we might improve the level of protection if we could find a way to make it with the proper type of carbohydrate," Dr Berman said.

To remedy this issue, the researchers developed a cell line that was able to produce the glucans found on HIV envelope proteins. They did so using CRISPR/Cas9 gene editing technology to develop the MGAT CHO cell line, which paved the way for a more streamlined, less costly process to recover and purify proteins, according to the session.

"People used to think carbohydrates are not immunogenic, but HIV turns everything on its head, and it turns out that the most important antibodies are directed to this unusual carbohydrate," Dr Berman said. "We can now make vaccines with it for the first time, and we've created an improved version of the vaccine used in the RV144 trial. Our hope is that it will bring the efficacy up from 31% to greater than 50%, the level likely required for product registration."

Dr Berman concluded the continued use of AIDSVAX in clinical trials are due to difficulties with creating new HIV vaccines, which highlights a significant unmet need.

"They're still using that same old vaccine we made in the early 1990s. Although the stability and safety of the product is testament to the quality of the vaccine we made, new vaccines are required that take advantage of all that we have learned since that time," Dr Berman said. "It just emphasizes the need to find a more efficient way to make an HIV vaccine."