A possible new COVID-19 vaccine could be accessible for more of the
world
The protein subunit vaccine, which can be manufactured using engineered
yeast, has shown promise in preclinical studies

Date:
March 16, 2022
Source:
Massachusetts Institute of Technology
Summary:
A new protein subunit vaccine may offer an inexpensive,
easy-to-store, and effective alternative to RNA vaccines for
COVID-19.



FULL STORY ========================================================================== While many people in wealthier countries have been vaccinated against
Covid-19, there is still a need for vaccination in much of the world. A
new vaccine developed at MIT and Beth Israel Deaconess Medical Center
may aid in those efforts, offering an inexpensive, easy-to-store, and
effective alternative to RNA vaccines.


==========================================================================
In a new paper, the researchers report that the vaccine, which comprises fragments of the SARS-CoV-2 spike protein arrayed on a virus-like
particle, elicited a strong immune response and protected animals against
viral challenge.

The vaccine was designed so that it can be produced by yeast, using fermentation facilities that already exist around the world. The Serum Institute of India, the world's largest manufacturer of vaccines, is now producing large quantities of the vaccine and plans to run a clinical
trial in Africa.

"There's still a very large population that does not have access to Covid vaccines. Protein-based subunit vaccines are a low-cost, well-established technology that can provide a consistent supply and is accepted in many
parts of the world," says J. Christopher Love, the Raymond A. and Helen
E. St.

Laurent Professor of Chemical Engineering at MIT and a 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 a professor
at Harvard Medical School, are the senior authors of the paper, which
appears today in Science Advances. The paper's lead authors are MIT
graduate students Neil Dalvie and Sergio Rodriguez-Aponte, and Lisa
Tostanoski, a postdoc at BIDMC.

Optimizing manufacturability Love's lab, working closely with Barouch's
lab at BIDMC, began working on a Covid-19 vaccine in early 2020. Their
goal was to produce a vaccine that would be not only effective but
also easy to manufacture. To that end, they focused on protein subunit vaccines, a type of vaccine that consists of small pieces of viral
proteins. Several existing vaccines, including one for hepatitis B,
have been made using this approach.



==========================================================================
"In places in the world where cost remains a challenge, subunit vaccines
can address that. They could also address some of the hesitancy around
vaccines based on newer technologies," Love says.

Another advantage of protein subunit vaccines is that they can often
be stored under refrigeration and do not require the ultracold storage temperatures that RNA vaccines do.

For their subunit vaccine, the researchers decided to use a small
piece of the SARS-CoV-2 spike protein, the receptor-binding domain
(RBD). Early in the pandemic, studies in animals 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 chose 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 on its own.

The researchers also wanted to ensure that their vaccine could be
manufactured easily and efficiently. Many protein subunit vaccines are manufactured 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 pastoris, which 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 produced separately in yeast. To each
component, the researchers added a specialized peptide tag that binds
with a tag found on the other component, allowing RBD fragments to be
attached to the virus particles after each is produced.



========================================================================== Pichia pastoris is already used to produce vaccines in bioreactors around
the world. Once the researchers had their engineered yeast cells ready,
they sent them to the Serum Institute, which ramped up production rapidly.

"One of the key things that separates our vaccine from other vaccines
is that the facilities to manufacture vaccines in these yeast organisms
already exist in parts of the world where the vaccines are still most
needed today," Dalvie says.

A modular process Once the researchers had their vaccine candidate ready,
they tested it in a small trial in nonhuman primates. For those studies,
they combined the vaccine with adjuvants that are already used in other vaccines: either aluminum hydroxide (alum) or a combination of alum and
another adjuvant called CpG.

In those 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 vaccine. They also found that
when the animals were exposed to SARS-CoV-2, viral loads in vaccinated
animals were much lower than those seen in unvaccinated animals.

For that vaccine, the researchers used an RBD fragment that was based
on the sequence of the original SARS-CoV-2 strain that emerged in
late 2019. That vaccine has been tested in a phase 1 clinical trial in Australia. Since then, the researchers have incorporated two mutations
(similar to ones identified in the natural Delta and Lambda variants)
that the team previously found to improve production and immunogenicity compared to the ancestral sequence, for the planned phase 1/2 clinical
trials.

The approach of attaching an immunogen 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," Rodriguez-Aponte says. "That shows the modularity
of the process and how efficiently you can edit and make 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 could
not only prove useful for 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 variety of SARS-CoV-2 strains
or other coronaviruses.

"In principle, this modularity does allow for consideration of adapting
to new variants or providing a more pan-coronavirus protective booster,"
Love says.

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.


========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Neil C. Dalvie, Lisa H. Tostanoski, Sergio A. Rodriguez-Aponte,
Kawaljit
Kaur, Sakshi Bajoria, Ozan S. Kumru, Amanda J. Martinot, Abishek
Chandrashekar, Katherine McMahan, Noe B. Mercado, Jingyou Yu, Aiquan
Chang, Victoria M. Giffin, Felix Nampanya, Shivani Patel, Lesley
Bowman, Christopher A. Naranjo, Dongsoo Yun, Zach Flinchbaugh,
Laurent Pessaint, Renita Brown, Jason Velasco, Elyse Teow,
Anthony Cook, Hanne Andersen, Mark G. Lewis, Danielle L. Camp,
Judith Maxwell Silverman, Gaurav S.

Nagar, Harish D. Rao, Rakesh R. Lothe, Rahul Chandrasekharan,
Meghraj P.

Rajurkar, Umesh S. Shaligram, Harry Kleanthous, Sangeeta
B. Joshi, David B. Volkin, Sumi Biswas, J. Christopher Love,
Dan H. Barouch. SARS-CoV- 2 receptor binding domain displayed
on HBsAg virus-like particles elicits protective immunity in
macaques. Science Advances, 2022; 8 (11) DOI: 10.1126/sciadv.abl6015 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220316145733.htm

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