On April 19, Moderna announced that its first bivalent vaccine candidate, mRNA-1273.211 booster needle, showed better neutralizing antibody titers in all the variant strains of interest, including Omicron, compared with mRNA-1273 (Spikevax) booster needles. This advantage lasted for 6 months after boosting immunization against the Beta and Omicron variant strains: at 1 month and 6 months, the anti-Omicron neutralizing antibody titers under mRNA-1273.211 booster needles increased by 2.20-fold (95% CI: 1.74, 2.79) and 2.15-fold (95% CI: 1.66, 2.78) respectively compared with mRNA-1273 booster needles. In addition, the tolerance and safety of this bivalent booster needle is consistent with the approved 50 µg mRNA-1273 booster needle…
With reflection and discussion on COVID-19 vaccine booster needles, many public health researchers are looking for and studying influenza vaccine models to guide how to deal with the lasting threat of SARS-CoV-2, which may mean injections are given annually just like preventing seasonal flu. But just as scientists have long been pursuing a universal influenza vaccine that provides lasting protection against a variety of respiratory virus subtypes, the COVID-19 field is also looking for a "pan-" coronavirus vaccine that can withstand future SARS-CoV-2 variants and prevent the next outbreak.
Does of nonprofit organizations, government agencies and vaccine manufacturers have listed these vaccine candidates as the top research priorities (Table 1). Leading this work is Epidemic Prevention Innovation Alliance (CEPI) and National Institute of Allergy and Infectious Diseases (NIAID), which allocated $200 million and $43 million respectively to develop a "pan-" coronavirus vaccine that integrates multi-functions.
Table 1 | Some pan-coronavirus vaccines under development
Source: Nature
Each organization has different focus. For example, CEPI focuses on near-term product development and mainly supports platform development of small biotech companies. NIAID supports more basic immunologic discovery efforts in academia. But their shared overall goal promotes cooperation between these two types of organizations. In March, CEPI and NIAID announced the establishment of a joint scientific forum for researchers they funded to discuss progress and work together to develop safe and extensive protective vaccines. The first meeting is scheduled to be held on April 25.
is being considered with a variety of vaccine design and delivery strategies. They include techniques based on mRNA and protein nanoparticles. Some candidate vaccines only target spike proteins that allow coronavirus to enter host cells, while others target other components of the viral proteome. Some studies aim only to improve antibody responses, while others focus on cellular immunity. Some researchers are confident about the coronavirus vaccine, but many researchers believe there is too much immunology unknown. The failure of a universal vaccine for influenza and HIV has signaled a thorn in the road ahead for decades.
clear direction, the term "pan-coronavirus" is used to describe many ongoing vaccine development work, but its meaning is vague. First, a modified COVID-19 vaccine designed to resist any mutant form of the SARS-CoV-2 virus may be more suitable for what is called a pan-mutant COVID-19 vaccine. But when experiments showed that it had some degree of cross-protection for SARS-CoV-1, some vaccine developers quickly adopted the broader pan-coronavirus label.
In a more inclusive (for multiple viruses) vaccine designed specifically, pan-coronavirus also has different meanings. Few scientists are developing true universal vaccine candidates that can withstand all 4 major coronavirus lineages. Instead, most targets are either to include all subgenus sarbecoviruses of SARS-like viruses or to be the larger branch of the family tree, which also includes pathogens that cause Middle East Respiratory Syndrome (MERS) and some seasonal coronaviruses that cause the common cold. Christopher da Costa, project leader at
CEPI, said the vague definition of cross-branch coronavirus protection has sparked a lot of "painful discussions". The organization finally selected “ broadly protecting ” to describe any vaccine against multiple coronaviruses, and “ variant targeting ” to describe the next generation of COVID-19 vaccines."Our vision is to control the number of targeted vaccines for future variants and have more extensive protective vaccines," da Costa said.
CEPI has announced funding of eight projects so far, and more projects are expected. Three of these vaccines target the emerging SARS-CoV-2, all of which use novel protein subunit technology to deliver part of the spike protein containing mutations in the target variant strain. One is from MigVax, taken orally with bacterial toxins as mucosal adjuvant; the other is from Affinivax, built around the antigen-polysaccharide binding platform; and the third is from Saskatchewan University vaccine and infectious disease tissue, which uses proprietary matrix to present antigens in a structured manner.
CEPI supports 5 other tasks aimed at defending against the wider coronavirus threat. Among them, three vaccines from BioNet, DIOSynVax and NEC will rely on computational modeling to identify novel vaccine antigens that can be used in mRNA delivery systems. The other two work is to develop multi-epitope, nanoparticle-based protein subunit vaccines, from SK bioscience and the Institute of Translational Health Science and Technology (THSTI), which collaborates with Panacea Biotec.
mutations continue. The "Mosaic" method helps
"Mosaic" transliterate it into mosaic. As the name suggests, the Mosaic vaccine uses mosaic to design vaccines to deal with high mutant viruses.
Among the five widely protective vaccines in the CEPI product portfolio, the SK candidate vaccine has made the fastest progress. Backed by CEPI's $50 million support, a vaccine called GBP511 (based on SK experimental COVID-19 vaccine GBP510) is undergoing a Phase III trial. It displays 60 parts of spike protein receptor binding domain (RBD) in trimer form to induce a potent immune response.
GBP510 only includes RBD from the original SARS-CoV-2 strain, but GBP511 uses the "Mosaic" method to present more antigens. It shows 3 or 4 RBDs from viruses infected with humans and bats (from all 3 branches of the sarbecovirus phylogenesis) to generate cross-reactive B cells that will bind to conserved epitopes shared by different RBDs. This multivalent antigen presentation should lead to the selective activation and expansion of immune cells with broad protection capabilities. Academic collaborators of
SK published a paper on Cell in September 2021, demonstrating the RBD nanoparticle vaccine inducing widespread protective sarbecovirus immunity in mice and monkey proof-of-concept experiments (below). South Korean biotech companies are preparing to launch their first human study by the end of 2023.
In addition, Pamela Bjorkman, a structural biologist at Caltech, has developed a similar mosaic RBD nanoparticle structure, and the related research was published in Science in January 2021. Its core uses the same icosahedral nanoparticles, but is decorated with RBD from eight sarbecoviruses viruses (6 of which infected bats, one infected pangolin, and one from the beta variant of SARS-CoV-2).
In Bjorkman's vaccine, RBD is randomly arranged, and the probability that the same antigen is adjacent to each other is very low. In contrast, SK's self-assembled nanoparticles use 3 sets of non-randomly organized RBDs. This structural difference may affect the possibility of stimulating cross-reactive antibody responses. "If they are randomly distributed, B cells that bind to more conservative regions of the receptor binding domain should be activated," Bjorkman said. A study published by Bjorkman's team in March on the preprint platform bioRxiv supports this conclusion. She is seeking financial support to push the candidate into clinical trials.
Going further, obtaining immunity breadth
Military Institute, Silver Spring City, Maryland is developing an adjuvant nanoparticle candidate vaccine prepared by binding a self-oligomeric protein called ferritin to a pre-fusion stable version of the SARS-CoV-2 spike protein. The results of the Phase I clinical study with 29 participants are expected to be announced in the coming weeks.
researchers call it a pan-coronavirus vaccine because in mice and monkey studies, the vaccine induces a powerful humoral and cellular-mediated immune response to the target SARS COV-2 variant strain and SARS-CoV-1. After the initial vaccination of two doses of the COVID-19 vaccine, the vaccine expanded its immunity as a booster shot.
Last year, Duke University immunologist Barton Haynes and colleagues, led by Ralph Baric, a virologist at the University of North Carolina, described a strategy to expand the benefits of mRNA platforms. They designed a coding sequence for a chimeric protein that assembles different parts of the spike protein (RBD, N-terminal domain and S2 subunit) of the sarbecoviruses virus that infect humans and bats. These mRNA sequences are packaged in lipid nanoparticles, which ultimately trigger a wide range of protective effects in mice. "This is an alternative to the mosaic method that can obtain a wide range of immune responses," Haynes said. "In principle, the same sequence can be encoded in self-amplified RNA, which enables lower dose regimens and better immune responses." Haynes’ team is exploring the use of this structure that contains both antigenic sequences and the mechanisms required by RNA to replicate itself.
continues to go deeper, clarify the rules of the game
Duke's projects mainly tend to platform development, but the other three NIAID's pan-coronavirus vaccine program are benefiting projects in Briggen and Women's Hospital, University of Wisconsin-Madison, and Rockefeller University, are more concerned about basic immunology issues. Project leader Jennifer Gordon pointed out that there are still many scientific unknowns. Hopefully, through a better understanding of the natural immune response to coronavirus infection, a better vaccine design will eventually be produced.
Last year, immunologist Duane Wesemann and colleagues at Briggen and Women's Hospital identified a potential antigenic target, the S2 domain of the spike protein conserves the stem, and the antibodies produced are related to reduced COVID-19 mortality, faster recovery after the disease subsides, and enhanced immune persistence (below). These antibodies also enhance the recognition breadth of beta coronaviruses, but they provide less neutralization than antibodies against spike proteins that are more variable in the head (targets of all first-generation COVID-19 vaccines). Therefore, more work is needed to determine which conditions are best suited for a wide range of protective vaccines to prevent the spread of zoonotic diseases.
researchers who aim to guide the immune responses in the stem area of hemagglutinin, a major conservative protein target for universal influenza vaccines. Given the many setbacks in the field, Wesemann hopes coronavirus researchers remain empty-cup mentality about the immune disorders in front of them.
In addition, it is particularly worth paying attention to how the immune quality of T cells affects the protective efficacy. Many researchers predict that for a pan-coronavirus vaccine to succeed, it must provide strong and broad protection through multiple T-cell subpopulations and antibody-mediated pathways. "To truly have a highly efficient vaccine, it is necessary to be able to induce neutralizing antibodies and T cells at the same time," said Corey Casper, president and CEO of Advanced Health Institute.
Casper is working closely with Immunity Bio to develop a dual antigen vaccine containing the spike protein and nucleocapsid (N) components. Nucleocapsid protein, an internal RNA-binding protein, has long been regarded as an important target for T-cell responses and may provide extensive protection.
Immunity Bio's first product is built around the human adenovirus serotype 5 (Ad5) platform and is currently being tested as a booster shot in subjects of Johnson & Johnson's spike-only adenovirus vector vaccine. But in addition to considering spike protein, the company has also developed a “mix-and-match” delivery strategy to improve results. A study published on the preprint platform, the company showed that in mouse experiments, saRNA-Prime and Ad5 enhancement appeared to enhance the durability and breadth of humoral and cellular immunity. This reflects the acceptance of the heterologous prime immune regimen of the first generation of COVID-19 vaccines, which will confer wider efficacy against the SARS COV-2 mutant strain.
So far, it is worth mentioning that at the beginning of this year, a study published by Zhu Fengcai, deputy director of the Jiangsu Center for Disease Control and Prevention, published on Nature medicine by the team of Zhu Fengcai, deputy director of the Jiangsu Provincial Center for Disease Control and Prevention, showed that after two doses of inactivated vaccine, the Ad5 adenovirus vector new crown vaccine was sequentially strengthened, with good safety and better antibody levels than homologous enhancement, which can effectively neutralize the mutant strains. After sequential vaccination, the human body's cellular immune response is significantly stimulated, which plays an important role in activate the re-response of cells in the body and effectively clearing cells infected by the virus.
Other companies that are surpassing spike-only design include TechImmune, ConserV Bioscience and Gritstonebio. The challenges faced by these companies are as Gaurav Gaiha, an immunologist at the Ragon Institute, suggests that finding mutation-restricted T cell epitopes to achieve "cross recognition" and high immunogenicity of the coronavirus.
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Without the threat of new epidemics and the budget of Operation Warp Speed at all costs, the development of the pan-coronavirus vaccine cannot move forward at the thrilling speed of the 2020 vaccine race. However, scientific and technological advances over the past two years have driven the development of this field. Researchers believe finding a vaccine that has a wide range of protective effects on coronavirus will not be as difficult as it is for HIV or influenza.
This article is from the Medical Rubik's Cube
