Biomaterial vaccines ward off broad range of bacterial infections and
septic shock
Date:
July 8, 2021
Source:
Wyss Institute for Biologically Inspired Engineering at Harvard
Summary:
Researchers have developed a biomaterial-based infection vaccine
(ciVAX) approach as a solution that could be broadly applied to
challenges in infection medicine.
FULL STORY ========================================================================== Current clinical interventions for infectious diseases are facing
increasing challenges due to the ever-rising number of drug-resistant
microbial infections, epidemic outbreaks of pathogenic bacteria,
and the continued possibility of new biothreats that might emerge in
the future. Effective vaccines could act as a bulwark to prevent many
bacterial infections and some of their most severe consequences, including sepsis. According to the Centers of Disease Control and Prevention (DCD),
"each year, at least 1.7 million adults in America develop sepsis. Nearly 270,000 Americans die as a result of sepsis [and] 1 in 3 patients who
dies in a hospital has sepsis." However, for the most common bacterial pathogens that cause sepsis and many other diseases, still no vaccines
are available.
==========================================================================
Now, as reported in Nature Biomedical Engineering, a multi-disciplinary
team of researchers at Harvard's Wyss Institute for Biologically Inspired Engineering and John A. Paulson School for Engineering and Applied
Sciences (SEAS) developed a biomaterial-based infection vaccine (ciVAX) approach as a solution that could be broadly applied to this pervasive
problem. ciVAX vaccines combine two technologies that are currently in
clinical development for other applications, and that together enable
the capture of immunogenic antigens from a broad spectrum of pathogens
and their incorporation into immune cell- recruiting biomaterial
scaffolds. Injected or implanted under the skin, ciVAX vaccines then
reprogram the immune system to take action against pathogens.
"The protective powers of the vaccines that we have designed and tested so
far and the immune responses they stimulated are extremely encouraging,
and open up a wide range of potential vaccine applications ranging from
sepsis prophylaxis to rapid measures against future pandemic threats
and biothreats, as well as new solutions to some of the challenges in veterinary medicine," said corresponding author David Mooney, Ph.D,
who is a Founding Core Faculty member at the Wyss Institute and leads
the Institute's Immuno-Materials Platform. He also the Robert P. Pinkas
Family Professor of Bioengineering at SEAS.
In their study, the researchers successfully tested ciVAX technology as
a protective measure against the most common causes of sepsis, including
Gram- positive S. aureus and Gram-negative E. coli strains. Highlighting
the technology's potential, they found that a prophylactic ciVAX
vaccine, protected all vaccinated mice against a lethal attack with an antibiotic-resistant E.
coli strain, while only 9% of unvaccinated control animals survived. In
a pig model of septic shock induced by a different human E. coli isolate,
a ciVAX vaccine prevented the development of sepsis in all four animals,
while four unvaccinated animals developed severe and sudden sepsis within
12 hours.
Finally, using an approach that mimicked a ring vaccination protocol
in human or animal populations, a CiVax vaccine, when loaded with pathogen-derived material isolated from animals infected with one lethal
E.coli strain, was able to cross-protect animals against a different
lethal E. coli strain.
"Our method captures the majority of glycoprotein (and glycolipid)
antigens from the pathogens, and presents these in their native form
to the immune system, giving us access to a much larger spectrum of
potential antigens than vaccines consisting of single or mixtures of recombinant antigens," said co- first author and Wyss Lead Senior Staff Scientist Michael Super, Ph.D. "ciVAX vaccines against known pathogens
can be fabricated and stored, but additionally, all components except
the bacterial antigens can be pre-assembled from shelf-stable cGMP
products. The complete vaccines can then be assembled in less than an
hour once the antigens are available, which gives this technology unique advantages over other vaccine approaches when rapid responses are called
for." Super conceived the ciVAX concept with co-first author Edward
Doherty, who as a former Lead Senior Staff Scientist worked with Mooney
on the Wyss' Immuno-Material platform on biomaterials-based vaccines
for cancer applications.
Super and Wyss Founding Director Donald Ingber, M.D., Ph.D., who also
authored the study, previously developed the pathogen capture technology
used in ciVAX, which is based on a native human pathogen-binding opsonin
-- Mannose Binding Lectin (MBL) -- that they fused to the Fc portion of
an Immunoglobulin to generate FcMBL. Recombinant FcMBL binds to more
than 120 different pathogen species and toxins, including bacteria,
fungi, viruses and parasites. In earlier efforts, the team applied FcMBL
to multiple diagnostic problems, and the technology is currently being
tested in a clinical trial by the Wyss startup BOA Biomedical as part
of a new sepsis treatment.
The second technology component of ciVAX component, the biomaterials-based vaccine technology, was developed as a conceptually new type of
cancer immunotherapy by Mooney and his group at the Wyss Institute and
SEAS, together with clinical collaborators at the Dana-Farber Cancer
Institute. Validated in a clinical trial in human cancer patients, a specifically designed cancer vaccine stimulated significant anti-tumor
immune responses. Novartis is currently working to commercialize
the vaccine technology for certain cancer applications, and a related biomaterials-based vaccine approach is being pursued by the Wyss startup Attivare Therapeutics, with Doherty and former Wyss researchers Benjamin
Seiler and Fernanda Langellotto, Ph.D., who also co- authored this study,
as founding members.
To assemble ciVAX vaccines, the team used FcMBL on magnetic beads to
capture inactivated bacterial carbohydrate-containing molecules, known
as Pathogen Associated Molecular Patterns (PAMPs), from the pathogen of
choice, and then simply mixed the complexes with particles of mesoporous
silica (MPS) and immune cell-recruiting and activating factors. Under
the skin, MPS forms a permeable, biodegradable scaffold that recruits
dendritic cells (DCs) of the immune system, reprograms them to present fragments of the captured PAMPs, and releases them again. The DCs then
migrate to nearby draining lymph nodes where they orchestrate a broad
immune response against the bacterial pathogen. The team found that
ciVAX vaccines rapidly enhanced the accumulation and activation of DCs
at injection sites and the numbers of DCs, antibody-producing B cells,
and different T cell types in draining lymph nodes, and thereby engineered effective pathogen-directed immune responses.
"Beyond the potential of reducing the risk for sepsis in and out of
hospitals, our ciVAX vaccine technology has the potential to save the
lives of many individuals threatened by a multitude of pathogens, in
addition to potentially preventing the spread of infections in animal populations or livestock before they reach humans. It is a terrific
example how Wyss researchers from different disciplines and experiences self-assemble around medical problems that urgently need to be solved to
create powerful new approaches," said Ingber who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital,
and Professor of Bioengineering at the Harvard John A. Paulson School
of Engineering and Applied Sciences.
========================================================================== Story Source: Materials provided
by Wyss_Institute_for_Biologically_Inspired_Engineering_at
Harvard. Original written by Benjamin Boettner. Note: Content may be
edited for style and length.
========================================================================== Journal Reference:
1. Michael Super, Edward J. Doherty, Mark J. Cartwright, Benjamin
T. Seiler,
Fernanda Langellotto, Nikolaos Dimitrakakis, Des A. White,
Alexander G.
Stafford, Mohan Karkada, Amanda R. Graveline, Caitlin L. Horgan,
Kayla R.
Lightbown, Frank R. Urena, Chyenne D. Yeager, Sami A. Rifai,
Maxence O.
Dellacherie, Aileen W. Li, Collin Leese-Thompson, Hamza Ijaz,
Amanda R.
Jiang, Vasanth Chandrasekhar, Justin M. Scott, Shanda L. Lightbown,
Donald E. Ingber, David J. Mooney. Biomaterial vaccines capturing
pathogen-associated molecular patterns protect against bacterial
infections and septic shock. Nature Biomedical Engineering, 2021;
DOI: 10.1038/s41551-021-00756-3 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2021/07/210708170354.htm
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