While many people in richer countries have been vaccinated against Covid-19, vaccination is still needed in large parts of the world. A new vaccine developed at MIT and Beth Israel Deaconess Medical Center can help in these endeavors and offer a cheap, easy to store and effective alternative to RNA vaccines.
In a new paper, the researchers report that the vaccine, which consists of fragments of the SARS-CoV-2 spike protein placed on a virus-like particle, elicited a strong immune response and protected animals from viral challenge.
The vaccine is designed so that it can be made from yeast using fermentation facilities that already exist around the world. The Serum Institute of India, the world’s largest producer of vaccines, is now producing large quantities of the vaccine and plans to run a clinical trial in Africa.
“There is still a very large population that does not have access to Covid vaccines. Protein-based subunit vaccines are an inexpensive, well-established technology that can deliver a consistent supply and are accepted in many parts of the world,” said J. Christopher Love, Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT and member of the Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT and Harvard.
Love and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC) and professor at Harvard Medical School, are the senior authors of the paper, which is published today in The progress of science. The paper’s lead authors are MIT graduate students Neil Dalvie and Sergio Rodriguez-Aponte, and Lisa Tostanoski, a postdoc at BIDMC.
Optimization of manufacturing ability
Love’s laboratory, working closely with Barouch’s laboratory at BIDMC, began work on a Covid-19 vaccine in early 2020. Their goal was to produce a vaccine that would not only be effective but also easy to manufacture. To that end, they focused on protein subunit vaccines, a type of vaccine made up of small pieces of viral protein. Several existing vaccines, including one against hepatitis B, have been prepared by this method.
“In places in the world where cost remains a challenge, subunit vaccines can solve it. They could also address some of the hesitation about vaccines based on newer technologies,” says Love.
Another advantage of protein subunit vaccines is that they can often be stored in a refrigerator and do not require the ultra-cold storage temperatures that RNA vaccines do.
For their subunit vaccine, the researchers decided to use a small piece of the SARS-CoV-2 peak protein, the receptor binding domain (RBD). Early in the pandemic, animal studies suggested that this protein fragment alone would not produce a strong immune response, so to make it more immunogenic, the team decided to display many copies of the protein on a virus-like particle. They selected the hepatitis B surface antigen as their scaffold and showed that when coated with SARS-CoV-2 RBD fragments, this particle generated a much stronger response than the RBD protein alone.
The researchers also wanted to ensure that their vaccine could be manufactured easily and efficiently. Many protein subunit vaccines are made using mammalian cells, which can be more difficult to work with. The MIT team designed the RBD protein so that it could be produced by the yeast Pichia pastoriswhich is relatively easy to grow in an industrial bioreactor.
Each of the two vaccine components – the RBD protein fragment and the hepatitis B particle – can be prepared separately in yeast. To each component, the researchers added a specialized peptide tag that binds to a tag found on the other component, allowing RBD fragments to bind to the virus particles after they are produced.
Pichia pastoris already used to produce vaccines in bioreactors around the world. When the researchers had their engineered yeast cells ready, they sent them to the Serum Institute, which increased production rapidly.
“One of the most important things that sets our vaccine apart from other vaccines is that the facilities for producing vaccines in these yeast organisms already exist in parts of the world where the vaccines are still most needed today,” says Dalvie.
A modular process
Once the researchers had their vaccine candidate ready, they tested it in a small experiment with non-human primates. For these studies, they combined the vaccine with adjuvants already used in other vaccines: either aluminum hydroxide (alum) or a combination of alum and another adjuvant called CpG.
In these studies, the researchers showed that the vaccine generated antibody levels similar to those produced by some of the approved Covid-19 vaccines, including the Johnson and Johnson vaccines. They also found that when the animals were exposed to SARS-CoV-2, the viral load in vaccinated animals was much lower than that seen in unvaccinated animals.
For that vaccine, the researchers used an RBD fragment based on the sequence of the original SARS-CoV-2 strain that appeared in late 2019. That vaccine has been tested in a Phase 1 clinical trial in Australia. Since then, researchers have incorporated two mutations (similar to those identified in the natural Delta and Lambda variants) that the team previously found to improve production and immunogenicity compared to the ancestral sequence, to the planned phase 1/2 clinical trials. experiments.
The approach of attaching an immunogenic RBD to a virus-like particle offers a “plug and display” -like system that could be used to create similar vaccines, the researchers say.
“We could make mutations that were seen in some of the new variants, add them to the RBD, but keep the whole framework the same and make new vaccine candidates,” says Rodriguez-Aponte. “It shows the modularity of the process and how effectively you can edit and create new candidates.”
If the clinical trials show that the vaccine provides a safe and effective alternative to existing RNA vaccines, the researchers hope that it can not only prove useful in vaccinating people in countries that currently have limited access to vaccines, but also enable the creation of boosters that would offer protection against a wider range of SARS-CoV-2 strains or other coronaviruses.
“In principle, this modularity allows you to consider adapting to new variants or provide a more pan-coronavirus-protective booster,” says Love.
Researchers from the Serum Institute and SpyBiotech also contributed to the paper. The research was funded by the Bill and Melinda Gates Foundation and the Koch Institute Support (core) Grant from the National Cancer Institute.