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Nanoparticle vaccine protects against various mutants and related viruses that cause COVID-19–ScienceDaily

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A new type of vaccine includes a variety of SARS-CoV-2 variants, including SARS-CoV-2 variants in mice and monkeys, according to a study led by a researcher at the Pamela Bjokman Institute at the California Institute of Technology, Professor of Biology, David Baltimore. To provide protection against beta corona virus and bioengineering.

Betacoronaviruses, including those that caused the SARS, MERS, and COVID-19 pandemics, are a subset of coronaviruses that infect humans and animals. The vaccine functions by presenting to the immune system a fragment of the peplomer protein from SARS-CoV-2 and seven other SARS-like beta coronaviruses attached to the protein nanoparticle structure, a wide range of cross-reactive antibodies. Induces production. In particular, when vaccinated with this so-called mosaic nanoparticles, the animal model was protected from the additional coronavirus SARS-CoV, which is not one of the eight represented by the nanoparticle vaccine.

“Animal vaccinated with Mosaic 8 nanoparticles induced antibodies that recognize beta coronavirus strains such as SARS that we evaluated,” said Alexander, a postdoc researcher at the California Institute of Technology. Cohen (PhD ’21) is the co-lead author of the new study. “Some of these viruses may be associated with strains that cause betacoronavirus outbreaks, such as the following SARS, so what we really want is the entire group of this virus. It’s a target. We believe we have it. “

The study is published in a journal article Chemistry July 5th.

“SARS-CoV-2 has been proven to be able to create new variants that have the potential to prolong the global COVID-19 pandemic,” said a professor at the Markin Institute in Biology and Biotechnology. Björkman, who is also an executive officer of the company, says. “Furthermore, the fact that the three beta coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have been released from animal hosts to humans over the last 20 years indicates the need to create a broadly defensive vaccine. I am. “

Björkman states that such extensive protection is needed. “Of the vast number of viruses in animals, it is unpredictable which virus will evolve to infect humans and cause another epidemic or pandemic. Which animal virus will evolve to infect and spread humans. An all-in-one vaccine that protects beta coronaviruses such as SARS, whether enabled or not. This type of vaccine also protects against current and future SARS-CoV-2 variants without renewal.

How it works: A vaccine consisting of spike domains from 8 different SARS-like coronaviruses

Vaccine technology that attaches viral fragments to protein nanoparticles was first developed by a collaborator at the University of Oxford. The basis of this technique is a small cage-like structure (“nanoparticles”) composed of proteins designed to have “sticky” appendages on the surface, on which researchers tag. Attached viral proteins can be attached. These nanoparticles can be prepared to display only one virus fragment (“homotype” nanoparticles) or several different virus fragments (“mosaic” nanoparticles). When injected into animals, nanoparticle vaccines present these viral fragments to the immune system. This induces the production of antibodies, immune system proteins that recognize and repel specific pathogens, and cell-mediated immune responses involving T lymphocytes and congenital immune cells.

In this study, researchers selected eight different SARS-like beta coronaviruses-SARS-CoV-2, the virus that caused the COVID-19 pandemic, and seven that could initiate a human pandemic. Includes related animal viruses — and fragments from those eight viruses were attached to the nanoparticle scaffold. The team selected specific fragments of the viral structure called the receptor-binding domain (RBD) that are important for coronavirus to invade human cells. In fact, human antibodies that neutralize coronavirus are primarily targeted at the viral RBD.

By targeting common features of the viral RBD, such vaccines produce antibodies that widely recognize betacoronaviruses such as SARS and repel mutants, in addition to those presented in nanoparticles. The idea is that you can guide your body to do so. This design is based on the idea that the diversity and physical placement of RBDs on nanoparticles concentrates the immune response on some of the RBDs shared throughout the SARS family of coronaviruses and achieves all immunity. increase. The data reported in Science today show the potential effectiveness of this approach.

Design of experiments to measure vaccine protection in mice

The resulting vaccine (here called Mosaic-8) consists of RBDs from eight coronaviruses. Previous experiments led by the Björkmann Institute have shown that mosaic-8 causes mice to produce antibodies that respond to various coronaviruses in laboratory dishes (Cohen et al., 2021). , Science). A new study led by Cohen, from this study, shows whether vaccination with the Mosaic 8 vaccine can induce protective antibodies in living animals during attacks (in other words, infection) with SARS-CoV-2 or SARS-CoV. The purpose is to confirm. ..

The team provided how much protection against infection by nanoparticles covered with various coronavirus fragments (mosaic-8) and nanoparticles covered only with SARS-CoV-2 fragments (“homotype” nanoparticles). The purpose was to compare what was done.

The team conducted three sets of experiments with mice. One was the control, which inoculated mice with only bare nanoparticle cage structures without virus fragments attached. Mice in the second group were injected with homomorphic nanoparticles covered exclusively with SARS-CoV-2RBD, and the third group was injected with mosaic 8 nanoparticles. One of the goals of the experiment was to see if inoculation with mosaic-8 protects animals from SARS-CoV-2 to the same extent as homozygous SARS-CoV-2 immune animals. The second goal was to assess protection from so-called “mismatched viruses”. This was not represented by RBD on Mosaic 8 nanoparticles.

In particular, the eight strains of coronavirus covering mosaic nanoparticles were intentionally free of SARS-CoV, the virus that caused the first SARS pandemic in the early 2000s. Therefore, the team also aims to investigate the degree of protection against attacks by the original SARS-CoV virus, which can be used to remove unknown SARS-like betacoronaviruses that can spread to humans. Represents.

The mice used in the experiment were genetically engineered to express the human ACE2 receptor, a receptor on human cells used by SARS-CoV-2 and related viruses to invade cells during infection. rice field. This animal challenge model dies when unvaccinated mice are infected with a beta coronavirus such as SARS, providing rigorous testing to assess potential protection from human infection and disease.

Mosaic vaccine protects mice from betacoronaviruses like SARS

As expected, mice inoculated with the naked nanoparticle structure died when infected with SARS-CoV or SARS-CoV-2. Mice inoculated with homozygous nanoparticles coated solely with SARS-CoV-2 RBD were protected from SARS-CoV-2 infection but died from exposure to SARS-CoV. These results indicate that current homologous SARS-CoV-2 nanoparticle vaccine candidates being developed elsewhere are effective against SARS-CoV-2, but like other SARS crossing from animal reservoirs. A variant suggesting that it may not be widely protected against the beta coronavirus or future SARS-CoV-2.

However, all mice inoculated with Mosaic 8 nanoparticles survived both SARS-CoV-2 and SARS-CoV challenges and had no weight loss or other serious medical conditions.

Studies of non-human primates have also confirmed the effectiveness of the mosaic vaccine.

The team then conducted a similar challenge experiment with non-human primates. This time, we used Mosaic 8, the most promising vaccine candidate, and compared the effects of Mosaic 8 vaccination with and without vaccination in an animal challenge study. When inoculated with Mosaic 8, animals show little or no detectable infection when exposed to SARS-CoV-2 or SARS-CoV, and Mosaic 8 vaccine candidates protect current and future variants of the virus. It shows the possibility. It causes a pandemic of COVID-19 and also causes potential future viral spillover of betacoronaviruses such as SARS from animal hosts.

Importantly, in collaboration with virologist Jesse Bloom (PhD ’07) at the Fred Hutchinson Cancer Research Center, the team teamed up with a diverse set of beta coronaviruses such as other SARS-induced antibodies that are induced by mosaic-8. We found that we are targeting the most common elements of RBD in — the so-called “conserved” portion of RBD-so that the virus is a new variant of SARS-CoV-2 or like SARS in animals. It provides evidence of a hypothesized mechanism that is effective against the beta coronavirus. In contrast, homologous SARS-CoV-2 nanoparticle injections elicit antibodies primarily to the strain-specific RBD region, and these types of vaccines protect against SARS-CoV-2 but are new. It suggests that it does not protect against developing variants or potential animal viruses.

As a next step, Bjorkman et al. Will evaluate mosaic 8 nanoparticle immunization in humans in a Phase 1 clinical trial supported by the Coalition for Epidemic Preparedness Initiative (CEPI). In preparation for a clinical trial that enrolls most people who have been vaccinated and / or previously infected with SARS-CoV-2, the Bjokman Institute has established a current COVID-of previously vaccinated animals. We are planning a preclinical animal model experiment to compare immune responses. 19 A vaccine against an immunologically naive animal response to SARS-CoV-2 infection or vaccination.

“Since the beginning of the pandemic, we have been discussing the need for diversity in vaccine development,” said Dr. Richard J. Hatchet, CEO of CEPI. “The breakthroughs shown in Björkman’s lab show great potential for strategies to fully pursue new vaccine platforms and may overcome the hurdles posed by new variants. We are pleased to announce that CEPI will support this new approach to pandemic prevention in Phase I. Clinical trials. Acceleration of research achieved after being funded by Welcome Leap is our relationship with them today. The non-human primate data is very encouraging and we are pleased to be able to support the next stage of the study. “

Wellcome Leap provided significant funding at a critical time to accelerate technological development at the California Institute of Technology, reducing the schedule for reaching Phase 1 clinical trials by more than 18 months. Regina E. Dugan (PhD ’93), CEO of Wellcome Leap, said:

The title of this article is “Mosaic RBD nanoparticles protect against attack by various salvecoviruses in animal models”. Neeltjevan Doremalen of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) Rocky Mountain Laboratories is the co-lead author with Cohen.

An additional co-author of the California Institute of Technology is research scientist Jennifer Keef. Chengcheng Fan, postdoctoral fellow in biology and biotechnology. Priyanthi Gnanapragasam, research engineer. Former research engineer Risa Tsunoya. Anthony P. West Jr., Senior Research Specialist. Former research engineer Yu Lee; Hangao, research engineer. Former graduate student Claudia Jette (PhD ’22).

Other co-authors are Fred Hutchinson Cancer Research Center Arisong Greenie, Tyler Star, and Jesse Bloom. BIOQUAL’s Hanne Andersen, Ankur Sharma, Mark Lewis; Jonathan Schultz, Greg Saturday, Vincent Münster of the Rocky Mountain National Institute. Tiong Tan and Alain Townsend from Oxford University.

This preclinical vaccine validation study was built directly on the initial development and principle empirical studies funded by Welcome Leap and funded early in the pandemic by the Markin Institute of Translation Medicine at the California Institute of Technology. Other coronavirus studies underway at the Bjorkman Group are supported by the Bill & Melinda Gates Foundation and George Mason Fast Grant.

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