Virus World

Repair of lung injury due to viral infection can be facilitated by nanoparticle-delivered mRNA targeting TGF-βR2 signaling. Respiratory infections, such as those caused by SARS-CoV-2 or influenza, can damage the lungs’ delicate network of capillary blood vessels, compromising oxygen delivery and carbon dioxide removal. To overcome this damage, the lungs depend on the regenerative capacities of vascular endothelial cells. As valuable as these cells are, they can, according to University of Pennsylvania scientists, benefit from a little help. The scientists, led by Andrew Vaughan, PhD, focused on a repair pathway involving vascular endothelial growth factor α (Vegfa) and the TGF-β receptor 2 (TGF-βR2). Using animal models and human tissue samples, the scientists showed that delivering Vegfa via lipid nanoparticles (LNPs) greatly enhances modes of repair for damaged blood vessels. “Mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair,” the article’s authors wrote. “Loss of endothelial Tgfbr2 prevented autocrine Vegfa expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange.” “We developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP),” the authors continued. “Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of endothelial cell Tgfbr2 deficiency during influenza injury.”

Vaughan’s team and other investigators had previously shown that endothelial cells are among the unsung heroes in repairing the lungs after viral infections. But Vaughan’s team noted that its work demonstrated that a “more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium” could inform efforts to facilitate therapeutic vascular repair. “Here we’ve identified and isolated pathways involved in repairing this tissue, delivered mRNA to endothelial cells, and consequently observed enhanced recovery of the damaged tissue,” Vaughan said. “These findings hint at a more efficient way to promote lung recovery after diseases like COVID-19.” The team found Vegfa’s involvement in this recovery, while building on work in which they used single-cell RNA sequencing to identify TGF-βR2 as a major signaling pathway. The researchers saw that when TGF-βR2 was missing, it stopped the activation of Vegfa. This lack of signal made the blood vessel cells less able to multiply and renew themselves, which is vital for the exchange of oxygen and carbon dioxide in the tiny air sacs of the lungs. “We’d known there was a link between these two pathways, but this motivated us to see if delivering Vegfa mRNA into endothelial cells could improve lung recovery after disease-related injury,” said first author Gan Zhao, PhD, a postdoctoral researcher in the Vaughan laboratory. The Vaughan laboratory then reached out to Michael J. Mitchell, PhD, of the School of Engineering and Applied Science, whose laboratory specializes in LNPs, to see if delivery of this mRNA cargo would be feasible.

“LNPs have been great for vaccine delivery and have proven incredibly effective delivery vehicles for genetic information,” said Mitchell, who is an associate professor of bioengineering at Penn Engineering and a co-author of the paper. “But the challenge here was to get the LNPs into the bloodstream without them heading to the liver, which is where they tend to congregate as its porous structure lends favor to substances passing from the blood into hepatic cells for filtration. So, we had to devise a way to specifically target the endothelial cells in the lungs.” The Mitchell laboratory’s LNPs proved effective in delivering Vegfa into endothelial cells, and as a result, the researchers saw a marked improvement in vascular recovery in their animal models. Within the animal models, the researchers saw improved oxygen levels, and in some, the treatment helped them recover their weight better than the control group. These treated mice also had less lung inflammation, shown by lower levels of certain markers in their lung fluid, and their lungs showed less damage and scarring, with more healthy blood vessels. “We’re looking forward to testing this delivery platform for other cell types in the lung, and it will be important to evaluate whether TGF-βR2 signaling is important in other injury contexts including chronic conditions like emphysema and chronic obstructive pulmonary disease,” Vaughan said. “With this proof-of-concept being well validated, we’re sure that we’ll pave the way for new mRNA-based strategies for treating lung injury.”

Published in January 31, 2024 in Science Translational Med:

https://doi.org/10.1126/scitranslmed.adg6229 

Software from Baidu Research yields jabs for COVID that have greater shelf stability and that trigger a larger antibody response in mice than conventionally designed shots. An artificial intelligence (AI) tool that optimizes the gene sequences found in mRNA vaccines could help to create jabs with greater potency and stability that could be deployed across the globe. Developed by scientists at the California division of Baidu Research, an AI company based in Beijing, the software borrows techniques from computational linguistics to design mRNA sequences with more-intricate shapes and structures than those used in current vaccines. This enables the genetic material to persist for longer than usual. The more stable the mRNA that’s delivered to a person’s cells, the more antigens are produced by the protein-making machinery in that person’s body. This, in turn, leads to a rise in protective antibodies, theoretically leaving immunized individuals better equipped to fend off infectious diseases. What’s more, the enhanced structural complexity of the mRNA offers improved protection against vaccine degradation. During the COVID-19 pandemic, mRNA-based shots against the SARS-CoV-2 coronavirus famously had to be transported and kept at temperatures below –15°C to maintain their stability. This limited their distribution in resource-poor regions of the world that lack access to ultracold storage facilities. A more resilient product, optimized by AI, could eliminate the need for cold-chain equipment to handle such jabs. The new methodology is “remarkable”, says Dave Mauger, a computational RNA biologist who previously worked at Moderna in Cambridge, Massachusetts, a maker of mRNA vaccines. “The computational efficiency is really impressive and more sophisticated than anything that has come before.”

Linear thinking

Vaccine developers already commonly adjust mRNA sequences to align with cells’ preferences for certain genetic instructions over others. This process, known as codon optimization, leads to more-efficient protein production. The Baidu tool takes this a step further, ensuring that the mRNA — usually a single-stranded molecule — loops back on itself to create double-stranded segments that are more rigid (see ‘Design optimization’). Known as LinearDesign, the tool takes just minutes to run on a desktop computer. In validation tests, it has yielded vaccines that, when evaluated in mice, triggered antibody responses up to 128 times greater than those mounted after immunization with more conventional, codon-optimized vaccines. The algorithm also helped to extend the shelf stability of vaccine designs up to sixfold in standard test-tube assays performed at body temperature. “It’s a tremendous improvement,” says Yujian Zhang, former head of mRNA technology at StemiRNA Therapeutics in Shanghai, China, who led the experimental-validation studies. So far, Zhang and his colleagues have tested LinearDesign-enhanced vaccines against only COVID-19 and shingles in mice. But the technique should prove useful when designing mRNA vaccines against any disease, says Liang Huang, a former Baidu scientist who spearheaded the tool’s creation. It should also help in mRNA-based therapeutics, says Huang, who is now a computational biologist at Oregon State University in Corvallis. The researchers reported their findings on 2 May in Nature1.

Optimal solutions

Already, the tool has been used to optimize at least one authorized vaccine: a COVID-19 shot from StemiRNA, called SW-BIC-213, that won approval for emergency use in Laos late last year. Under a licensing agreement established in 2021, the French pharma giant Sanofi has been using LinearDesign in its own experimental mRNA products, too. Executives at both companies stress that many design features factor into the performance of their vaccine candidates. But LinearDesign is “certainly one type of algorithm that can help with this”, says Sanofi’s Frank DeRosa, head of research and biomarkers at the company’s mRNA Center of Excellence. Another was reported last year. A team led by Rhiju Das, a computational biologist at Stanford School of Medicine in California, demonstrated that even greater protein expression can be eked out of mRNA — in cultured human cells at least — if certain loop patterns are taken out of their strands, even when such changes loosen the overall rigidity of the molecule2. That suggests that alternative algorithms might be preferable, says theoretical chemist Hannah Wayment-Steele, a former member of Das’s team who is now at Brandeis University in Waltham, Massachusetts. Or, it suggests that manual fine-tuning of LinearDesign-optimized mRNA could lead to even better vaccine sequences. But according to David Mathews, a computational RNA biologist at the University of Rochester Medical Center in New York, LinearDesign can do the bulk of the heavy lifting. “It gets people in the right ballpark to start doing any optimization,” he says. Mathews helped develop the algorithm and is a co-founder, along with Huang, of Coderna.ai, a start-up based in Sunnyvale, California, that is developing the software further. Their first task has been updating the platform to account for the types of chemical modification found in most approved and experimental mRNA vaccines; LinearDesign, in its current form, is based on an unmodified mRNA platform that has fallen out of favour among most vaccine developers.

A structured approach

But mouse studies and cell experiments are one thing. Human trials are another. Given that the immune system has evolved to recognize certain RNA structures as foreign — especially the twisted ladder shapes within many viruses that encode their genomes as double-stranded RNA — some researchers worry that an optimization algorithm such as LinearDesign could end up creating vaccine sequences that spur harmful immune reactions in people. “That’s kind of a liability,” says Anna Blakney, an RNA bioengineer at the University of British Columbia in Vancouver, Canada, who was not involved in the study. Early results from human clinical trials involving StemiRNA’s SW-BIC-213 suggest the extra structure is not a problem, though. In small booster trials reported so far, the shot’s side effects have proved no worse than those reported with other mRNA-based COVID-19 vaccines3. But as Blakney points out: “We’ll learn more about that in the coming years.”

Research Cited published in Nature (May 2, 2023):

https://doi.org/10.1038/s41586-023-06127-z 

An international team of researchers has used mRNA technology to develop an influenza vaccine that targets four proteins that tend to change little across viral strains. In their paper published in Proceedings of the National Academy of Sciences, the group describes their approach to developing a new kind of flu vaccine and how well it has worked in test mice.   Because the two main types of flu strains, A and B, adapt so quickly to annual vaccines, new ones have to be developed every year. This approach is not only expensive, but also hit-and-miss—the medical community sometimes encounters a surprise variant that their newly created vaccine cannot fight. Because of that, medical researchers have been looking for a better alternative. In this new effort, the researchers built on lessons learned from the pandemic. The two main vaccines developed to protect people against COVID-19 are based on messenger RNA technology (mRNA), in which pieces of genetic code are administered, prompting the immune system to produce proteins that target the SARS-CoV-2 virus should it appear.

To develop a similar type of vaccine for influenza, the researchers used multiple bits of genetic code to get the body to produce antigens for matrix protein 2, the stalk part of hemagglutinin, nucleoprotein and neuraminidase. The team then tested their vaccine on mice, none of which had ever been infected by the influenza virus. In all, 20 mice were injected with combinations of the new vaccine. Some were injected with a vaccine for just two of the mRNA segments, for example, while others got all four. They also injected some of the mice more than once. Blood testing showed that all of the mice produced some degree of an increase in antibody production, but only the mice who got the quadrivalent shot were fully protected, though there was one exception—the mice that got a monovalent vaccine with just nucleoprotein. The researchers also found that some of the combinations led to an increase in production of cytotoxic T cells, which prior research has shown play a major role in combating flu infections in both mice and humans.

Research cited published in P.N.A.S. (Nov. 2, 2022):

https://doi.org/10.1073/pnas.2206333119 

mRNA technology may be uniquely positioned to tackle a major hurdle for HIV vaccines: the elicitation of broadly cross-reactive neutralizing antibodies. A preclinical study takes the first step toward this goal.  The remarkable success of mRNA vaccines against COVID-19 has been nothing short of miraculous. Whether this unique technology platform can be used to tackle the more complex task of developing a vaccine against human immunodeficiency virus (HIV) is now under intense scrutiny. In this issue of Nature Medicine, a preclinical study by Zhang et al. suggests that the mRNA platform may be up to the challenge1. The authors encapsulated mRNA encoding the HIV envelope glycoprotein (Env) (the equivalent of the SARS-CoV-2 spike protein), together with the structural HIV group-specific antigen protein (Gag), in a lipid nanoparticle, to produce virus-like particles (VLPs) in vivo. These Env-expressing VLPs elicited broadly neutralizing antibodies (bNAbs) and other immune responses that were protective against viral challenge in a macaque model. Although the VLPs were not nearly as immunogenic or as efficacious as mRNA vaccines against COVID-19, these results are encouraging and illuminate a pathway toward inducing the higher and more-durable antibody responses needed to prevent infection with HIV. This is no small feat; Env is a formidable target that fails to induce the right kind of antibodies even in the majority of people who are infected with HIV. Unlike spike protein, which is relatively stable and contains just a few immunodominant epitopes (mostly restricted to the receptor-binding domain), Env is a complex trimeric protein with multiple dispersed antibody epitopes — many of which are conformational and heavily coated in sugars that shield them from antibody attack (Fig. 1). The ability to generate soluble trimeric Env proteins through the introduction of key mutations was a major advance in immunogen design, although these so-called ‘SOSIP proteins’ induced only autologous strain–specific neutralizing antibodies2. In the present study by Zhang et al., antibodies elicited by the Env–Gag mRNA were able to neutralize almost all members of a global panel of HIV isolates, classified as having a tier 2 phenotype1. This represents a major step forward for a vaccine against HIV, as this phenotype is typical of most circulating strains, which are difficult to neutralize due to a closed Env conformation.

It is likely that a number of factors contributed to the greater immunogenicity of the mRNA vaccine designed by Zhang et al.1. The endogenous expression of the native Env on the surface of a VLP would preserve conformational epitopes, and VLPs were also shown to contain double the number of Env molecules present in an HIV viral particle. Furthermore, mRNA continues to be expressed for several days after administration, providing ongoing immunostimulation3. Another potential advantage is the ability of VLPs to bind to antigen-presenting cells, which guarantees delivery of mRNA into the appropriate cells and the induction of follicular helper T cells that are crucial for B cell development in germinal centers4. Zhang et al. also chose an HIV Env sequence that lacks a glycan at position 276; this enabled better access to the B cell precursors of bNAbs that target the CD4-binding site on the viral envelope1. Indeed, Env–Gag mRNA elicited antibodies to that site and, interestingly, to many other HIV epitopes — a considerable improvement on the strain-specific ‘glycan-hole’ responses seen with SOSIP proteins. It will be important in future studies to isolate B cells from mRNA-immunized animals to ascertain whether they are capable of broad neutralization and if they carry the genetic features associated with known bNAb lineages. Although the results from Zhang et al.1 are encouraging for the HIV vaccine field, this is a complex and impractical protocol that requires multiple immunizations with high doses of mRNA. Moreover, the levels of bNAbs elicited in this study were extremely low and took a year to develop, and their role in protection from infection remains unclear. mRNA technology has only recently come of age; it was originally hampered by instability and unfavorable immunogenicity, but decades of research have solved these problems, and the advantages of mRNA as a vaccine platform continue to emerge5. These include rapid development, ease of manufacture and scalability, which offer advantages over the traditional vector-based or protein-based vaccines being pursued in the HIV field. For example, mRNA would enable testing of sequential immunization and lineage-based approaches that require multiple immunogens with minor but important sequence changes6. mRNA is also considerably cheaper to produce and can be modified as needed, an important consideration for rapidly mutating viruses like HIV. Among the vaccines against COVID-19, those based on the mRNA platform have superior immunogenicity and stimulate both B cell responses and T cell responses7,8. The precise mechanisms underlying mRNA immunogenicity, however, are still unknown, and much remains to be learned if they are to be optimized and applied to HIV prevention. Nonetheless, the vast amount of safety data available from mRNA vaccines against COVID-19 will probably contribute to streamlined regulatory approval processes for vaccines against HIV and other diseases.

Participants in the trial must be between the ages of 18 and 50 and not diagnosed with HIV.  Moderna is set to start human trials for its experimental mRNA HIV vaccine as early as Thursday, the first time such a trial has ever been conducted. 

The big picture: "There's a pressing need for new ways to prevent infection from viruses like HIV and influenza that conventional vaccines have struggled to address and to treat rare genetic diseases and cancers that kill millions each year," Axios' Alison Snyder writes. "Vaccines and therapies based on messenger RNA (mRNA) hold promise as a solution."

Details: To participate in the trial, participants have to be between the ages of 18 and 50 and not diagnosed with HIV. Moderna says it is looking for 56 participants.

What they're saying: "Even as we have shown that our mRNA-based vaccine can prevent Covid-19, this has encouraged us to pursue more-ambitious development programs within our prophylactic vaccines modality," said Moderna CEO Stéphane Bancel in January, when the company announced the vaccine, per Clinical Trials Arena.

Company says mutant coronavirus strains likely explain its candidate’s weak efficacy, but outside scientists question its “natural” approach.  The startlingly poor performance revealed this week for a COVID-19 vaccine made by the German company CureVac isn’t just a disappointment, it’s a scientific puzzle. The company blames the rapidly changing pandemic virus. But several outside researchers suspect the vaccine’s design is at fault. Many scientists and investors alike had expected CureVac’s candidate, which uses messenger RNA (mRNA) to code for the spike surface protein of SARS-CoV-2, had a good chance of becoming one of the most powerful new weapons against the pandemic. It relies on essentially the same novel mRNA technology as vaccines from the Pfizer-BioNTech collaboration and Moderna, which had more than 90% efficacy in their trials, and it holds some practical transportation and storage advantages over those rival shots. But preliminary data released Wednesday evening and discussed on a call with investors yesterday suggest the efficacy of the CureVac vaccine is a lackluster 47%—low enough that, if further data are equally disappointing, health regulators likely won’t authorize it for emergency use.  The efficacy trial enrolled some 40,000 people, about 75% in Latin America and 25% in Europe. The topline finding came from an interim analysis evaluating 134 participants who developed at least one COVID-19 symptom. Although the company did not give a breakdown, the reported 47% efficacy translates to roughly 88 cases in the placebo group and 46 among the vaccinated. “The results are sobering,” said Franz Werner-Haas, CureVac’s CEO. He stressed that the many SARS-CoV-2 variants now in circulation may explain the disappointing results. The vaccine’s mRNA was designed for a version of spike that was dominant among viruses early in the pandemic but has evolved through multiple mutations. “We are virtually fighting a different virus, different pandemic over the last 6 months,” Werner-Haas said. 

The trial scientists sequenced the virus in 124 participants who got sick and found 13 different variants. Only 1% of the infected people had a SARS-CoV-2 whose spike matched the mRNA used in the vaccine. “Demonstrating high efficacy in this unprecedented broad diversity of variants is quite challenging,” Werner-Haas said. Other efficacy trials have found that certain mutant strains of the coronavirus can compromise the ability of COVID-19 vaccines to protect against mild disease, but the variant that has most powerfully undermined other vaccines, Beta, was not seen in the CureVac study. In contrast, Alpha, first seen in the United Kingdom and one of the earliest variants of concern, caused 41% of the 124 cases overall and 91% of the 44 cases that occurred in Europe. Kathleen Neuzil of the University of Maryland School of Medicine doubts variants fully explain the poor performance of CureVac’s vaccine. Unlike CureVac’s mRNA shot, she says, the Pfizer-BioNTech and Moderna vaccines “work very well against Alpha.” She cautions that it’s difficult to compare trials of different vaccines, but says, “It’s just hard for me to believe that the variants could have this degree of effect.”  CureVac did not provide any data about how many of the infected in its efficacy trial developed severe disease. Other vaccines continue to prevent most hospitalizations and deaths even when variants reduce their protection against mild COVID-19. Some scientists trying to make sense of the CureVac result point to an earlier, phase 1 study of the vaccine. It showed that serum levels of so-called neutralizing antibodies, which prevent the virus from binding to cells, were relatively low in vaccine recipients compared with people who naturally became infected with the coronavirus. “It’s certainly a good possibility that the vaccine is just not immunogenic enough,” says John Moore, an immunologist at Weill Cornell Medicine who specializes in analyzing neutralizing antibodies.

The type of mRNA used by CureVac may undermine antibody formation, contends Drew Weissman of the University of Pennsylvania’s Perelman School of Medicine, who helped pioneer certain mRNA modifications used by in the Pfizer-BioNTech and Moderna vaccines. (Those companies license the technology, which may financially benefit the university and Weissman.) CureVac’s vaccine used an unmodified form of mRNA. When natural mRNA is injected into the body, it triggers the production of interferons, signaling molecules that can rev up the immune system. CureVac touted that as an advantage of its formulation. But Weissman notes interferons can also block the generation of T helper cells that, in turn, direct B cells to make antibodies. Pfizer and BioNTech and Moderna, in contrast, chemically altered the uracils, one of the four nucleotides that make up RNA, in their spike-encoding sequences. Weissman’s group had shown in 2018 that uracil-modified mRNA triggered potent neutralizing antibodies and other protective immune responses in animal models. He notes that a BioNTech study comparing modified and natural mRNA vaccines also found that the modifications boosted the antibody response.

Peter Kremsner of University Hospital Tübingen, who helped run the CureVac study, suggests another factor: too low a dose of vaccine. “I am uncertain what it was finally, natural uracil or only dose or both,” he says. Kremsner helped conduct CureVac’s phase 1 study, which compared the safety and immune responses generated by doses between 2 and 20 micrograms. The study revealed the company should not use the higher doses “because of intolerability, perhaps due to natural uracil?” he says. (Kremsner says he hopes to publish his work soon, but a preprint with some of the study’s data has already been posted.) CureVac settled on 12 micrograms, a dose that balanced the best safety profile with the highest level of neutralizing antibodies. (The Pfizer-BioNTech vaccine uses a 30-microgram dose and Moderna’s is 100 micrograms.) Other data presented at yesterday’s press conference suggest, however, that the design of the vaccine is more important than the dose. CureVac reported data from a monkey study that compared its current vaccine to a next-generation version, which is more stable inside of cells and made in collaboration with the pharmaceutical giant GlaxoSmithKline: The new candidate produced higher levels of the spike protein, triggering a 10-fold higher level of neutralizing antibodies. Dose-ranging studies of the Pfizer and Moderna vaccines have also found that higher mRNA doses offer relatively modest gains in antibody levels. Still, CureVac says it must wait for the final analysis of the current efficacy trial, expected to include more than 200 COVID-19 cases, before it makes a “strategic shift” to the second-generation vaccine. “For now, we are going full speed exactly where we are,” Werner-Haas said. “We are expecting the data to come within the next 3 weeks.”

CureVac's Press Release with update of results of Phase 2/3 trial available at:

https://www.curevac.com/en/2021/06/16/curevac-provides-update-on-phase-2b-3-trial-of-first-generation-covid-19-vaccine-candidate-cvncov/ 

The investigational vaccine known as mRNA-1273 was 94.1% efficacious in preventing symptomatic coronavirus disease 2019 (COVID-19), according to preliminary results from a Phase 3 clinical trial reported in the New England Journal of Medicine. The vaccine also demonstrated efficacy in preventing severe COVID-19. Investigators identified no safety concerns and no evidence of vaccine-associated enhanced respiratory disease (VAERD). The vaccine was co-developed by Moderna, Inc., a biotechnology company based in Cambridge, Massachusetts, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Moderna(link is external) and NIAID previously shared initial results from the COVE trial. On Dec. 18, 2020, the FDA issued an Emergency Use Authorization(link is external) allowing Moderna to make the vaccine available for the prevention of COVID-19 in adults in the United States. The trial was led by principal investigators Lindsey R. Baden, M.D. of Brigham and Women’s Hospital in Boston, Hana M. El-Sahly, M.D. of Baylor College of Medicine in Houston, and Brandon Essink, M.D., of Meridian Clinical Research. The trial was implemented under the U.S. government’s Operation Warp Speed program and supported by NIAID and the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response.

The trial began on July 27, 2020, and enrolled 30,420 adult volunteers at clinical research sites across the United States. Volunteers were randomly assigned 1:1 to receive either two 100 microgram (mcg) doses of the investigational vaccine or two shots of saline placebo 28 days apart. The average age of volunteers is 51 years. Approximately 47% are female, 25% are 65 years or older and 17% are under the age of 65 with medical conditions placing them at higher risk for severe COVID-19. Approximately 79% of participants are white, 10% are Black or African American, 5% are Asian, 0.8% are American Indian or Alaska Native, 0.2% are Native Hawaiian or Other Pacific Islander, 2% are multiracial, and 21% (of any race) are Hispanic or Latino. From the start of the trial through Nov. 25, 2020, investigators recorded 196 cases of symptomatic COVID-19 occurring among participants at least 14 days after they received their second shot. One hundred and eighty-five cases (30 of which were classified as severe COVID-19) occurred in the placebo group and 11 cases (0 of which were classified as severe COVID-19) occurred in the group receiving mRNA-1273. The incidence of symptomatic COVID-19 was 94.1% lower in those participants who received mRNA-1273 as compared to those receiving placebo.  Investigators observed 236 cases of symptomatic COVID-19 among participants at least 14 days after they received their first shot, with 225 cases in the placebo group and 11 cases in the group receiving mRNA-1273. The vaccine efficacy was 95.2% for this secondary analysis. There were no concerning safety issues with vaccination, according to the authors. Local reactions to the vaccine were generally mild. About 50% of participants receiving mRNA-1273 experienced moderate-to-severe side effects — such as fatigue, muscle aches, joint pain and headache — after the second dose, which resolved in most volunteers within two days.

Investigators also observed no evidence of VAERD among those who received mRNA-1273. This rare complication was seen in individuals vaccinated with a whole-inactivated respiratory syncytial virus (RSV) vaccine in the 1960s, before there was a capacity to define protein structures and measure immune responses with precision. VAERD can occur when a vaccine induces an immune response that is not strong enough to protect against infection. Although mRNA-1273 is highly efficacious in preventing symptomatic COVID-19, there is not yet enough available data to draw conclusions as to whether the vaccine can impact SARS-CoV-2 transmission. Preliminary trial data suggests there may be some degree of prevention of asymptomatic infection after a single dose. Additional analyses are underway of the incidence of asymptomatic infection and viral shedding post-infection to understand the vaccine’s impact on infectiousness. The authors concluded by discussing the unprecedented efficiency of the candidate vaccine’s development, noting, “this process demonstrates what is possible in the context of motivated collaboration among key sectors of society, including academia, government, industry, regulators and the larger community.”

Findings Published in NEJM (Dec. 30, 2020):

https://doi.org/10.1056/NEJMoa2035389

Pfizer and BioNTech are under a white-hot spotlight because their vaccine, by design, is likely to be the first to have any efficacy data. The announcement is both good news and bad news. Umer Raffat, a senior managing director at the investment bank Evercore ISI, wrote in an analyst note that the fact that Pfizer hasn’t conducted an interim analysis was “a good thing” because it means that, based on the details of the trial protocol, the vaccine had not failed to prevent more than 77% of Covid cases, the benchmark for success at this early juncture. But it also suggests that cases of Covid are being reported less frequently among participants in the Pfizer study than in the U.S. as a whole. That means that the study is progressing more slowly than Pfizer and its partner, BioNTech, originally expected. In August, Pfizer had thought that the first interim analysis could occur as early as September. Pfizer and BioNTech are under a white-hot spotlight because their Covid-19 vaccine, by design, is likely to be the first to have any efficacy data. But that first analysis will come when there have been a total of only 32 cases of Covid-19 across the company’s entire 42,000-volunteer study. It would be considered to be positive, Pfizer has said, if six or fewer of those 32 cases occurred in the group that received the vaccine, with the rest occurring in the group that received the placebo. The trial is expected to continue until 150 of the volunteers in the study have had Covid-19.

Pfizer CEO Albert Bourla set the goal of having a Covid-19 vaccine ready by October this spring, in what appeared to be a bid both to combat the pandemic and to make a statement about the company’s research prowess. Pfizer is in the midst of spinning off older, slower-growing parts of the company in a merger with Mylan, which will leave Bourla running a firm whose future will depend heavily on its research laboratories and the prospects of its experimental drugs.  The vaccine itself is expected to be a significant but not huge financial opportunity. Analysts at SVB Leerink estimate sales could peak at $3.5 billion in 2021, and then stabilize at $1.4 billion a year. In its third-quarter earnings, also announced Tuesday, Pfizer reported profits of $2.2 billion on sales of $12.1 billion. But the October time frame has put Pfizer squarely in the political maelstrom of the U.S. election, as President Trump repeatedly predicted that a vaccine would be available before Election Day. It has been clear for months that other companies developing Covid-19 vaccines, including Moderna, AstraZeneca, and Johnson & Johnson, had no chance of hitting that mark.

On Oct. 6, the Food and Drug Administration released new guidance on safety data that would be required before it would consider clearing a vaccine through an emergency use authorization, or EUA, its fastest path to making a vaccine available. The agency told drug makers not to file for an EUA until at least half the patients in their studies have been followed for two months. In an Oct. 16 public letter, Bourla confirmed that this would prevent Pfizer from filing for an EUA until the third week of November. At an advisory panel of outside experts the FDA held last week, the agency signaled that it was not certain it would grant an EUA for a vaccine until a sufficient amount of data had been accumulated to more fully understand the safety and efficacy of a vaccine prospect.

The companies started a large study of a vaccine candidate for Covid-19 aimed at securing approvals — but it’s not the one for which results were released. Pfizer and BioNTech are starting a large study of a vaccine candidate for Covid-19 aimed at securing approvals — but it’s not the one for which results were released earlier this month. The companies always said that they planned to pick from among four different candidates, all of which use a technology called messenger RNA to produce a protein on SARS-CoV-2, the virus that causes Covid-19. The vaccine is designed to lead the immune system to recognize the protein, and, it is hoped, to attack the virus. On July 1, the companies announced results in a preprint publication showing that one vaccine candidate, BNT162b1, prompted an immune response in patients. That vaccine encoded a key portion of the spike protein, which SARS-CoV-2 uses to enter cells. The vaccine being taken forward, BNT162b2, encodes an optimized version of the whole spike protein, which should lead to “more consistent responses across diverse populations and in older adults,” Pfizer said in a statement. Philip Dormitzer, a Pfizer vice president in charge of vaccines, said the selected vaccine appears to generate a stronger response, in part because it includes more of the spike protein. That could mean less variability in how people respond to the vaccine. It also seemed to cause fewer side effects. “It just seemed a bit milder,” Dormitzer said in an interview. “There were fewer reactions to immunization, and that was an important mark in its favor.”

The study, which began today, will recruit about 30,000 healthy volunteers between 18 and 85, randomizing half to get the vaccine and the rest to get placebo. Pfizer will recruit from about 120 sites in countries around the world, including the U.S., Germany, and Brazil. The primary goal is preventing patients from developing Covid-19, and the secondary endpoints include preventing severe cases of the disease and protecting volunteers against asymptomatic infections. The announcement came hours after Moderna began a 30,000-participant trial of its own. Like Pfizer and BioNTech, Moderna’s vaccine uses messenger RNA to compel the body to produce spike proteins, leading to an immune response that will ideally protect subjects from Covid-19. Pfizer and BioNTech said that they are on track to file for regulatory review as early as October, and that they plan to supply up to 100 million doses by the end of 2020 and 1.3 billion doses by the end of 2021.

A new study unveils a novel mechanism that allows viruses to produce unexpected proteins. Like a scene out of "Invasion of the Body Snatchers," a virus infects a host and converts it into a factory for making more copies of itself. Now researchers have shown that a large group of viruses, including the influenza viruses and other serious pathogens, steal genetic signals from their hosts to expand their own genomes. This finding is presented in a study published online today and in print June 25 in Cell. The cross-disciplinary collaborative study was led by researchers at the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai in New York, and at the MRC-University of Glasgow Centre for Virus Research in the UK.

The cross-disciplinary team of virologists looked at a large group of viruses known as segmented negative-strand RNA viruses (sNSVs), which include widespread and serious pathogens of humans, domesticated animals and plants, including the influenza viruses and Lassa virus (the cause of Lassa fever). They showed that, by stealing genetic signals from their hosts, viruses can produce a wealth of previously undetected proteins. The researchers labeled them as UFO (Upstream Frankenstein Open reading frame) proteins, as they are encoded by stitching together the host and viral sequences. There was no knowledge of the existence of these kinds of proteins prior to this study. These UFO proteins can alter the course of viral infection and could be exploited for vaccine purposes.

"The capacity of a pathogen to overcome host barriers and establish infection is based on the expression of pathogen-derived proteins," said Ivan Marazzi, PhD, Associate Professor of Microbiology at Icahn School of Medicine and corresponding author on the study. "To understand how a pathogen antagonizes the host and establishes infection, we need to have a clear understanding of what proteins a pathogen encodes, how they function, and the manner in which they contribute to virulence." Viruses cannot build their own proteins, so they need to feed suitable instructions to the machinery that builds proteins in their host's cells. Viruses are known to do this through a process called "cap-snatching," in which they cut the end from one of the cell's own protein-encoding messages (a messenger RNA, or mRNA) and then extend that sequence with a copy of one of their own genes. This gives a hybrid message to be read....

Original Study Published in Cell (June 25, 2020):

https://doi.org/10.1016/j.cell.2020.05.035

One of the first biotech companies to begin human trials of an experimental vaccine for the coronavirus is now ready to move onto the next phase of testing. On Thursday, Moderna announced that the Food and Drug Administration had cleared its application to proceed to a clinical trial involving about 600 people.

“The imminent Phase 2 study start is a crucial step forward,” Stéphane Bancel, Moderna’s chief executive, said in a statement. The main goal of this set of tests is to find out if the vaccine is safe and if positive results from the first few dozen volunteers in the first phase can be replicated in a much larger group. If it is successful, later studies, known as Phase 3 trials, will determine exactly how well the vaccine works. More than a dozen companies, including known vaccine producers like Johnson & Johnson, or Sanofi, are involved in a global race to develop a vaccine to tamp down the highly infectious coronavirus that has killed more than a quarter-million people around the world. Four Chinese companies have started testing their potential vaccines on humans, including CanSino Biologics, which announced the beginning of Phase 2 trials in early April. A few others, such as Pfizer and its German partner, BioNTech, are enrolling volunteers for combined Phase 1 and 2 trials.

Dr. Anthony Fauci, the nation’s leading expert on infectious diseases, has suggested that it would still take 12 to 18 months for a vaccine to be widely available to the public. There is no proven treatment, and many researchers and corporations around the world are pursuing remedies in addition to vaccines. Moderna’s vaccine candidate, called mRNA-1273, relies on genetic material known as messenger RNA, which carries the recipe for making proteins to tiny ribosome chefs inside cells. The vaccine is written with a very specific recipe — in this case for making the spike protein of the coronavirus.

Scientists have developed a new gene-therapy technique by transforming human cells into mass producers of tiny nano-sized particles full of genetic material that has the potential to reverse disease processes. Though the research was intended as a proof of concept, the experimental therapy slowed tumor growth and prolonged survival in mice with gliomas, which constitute about 80 percent of malignant brain tumors in humans. The technique takes advantage of exosomes, fluid-filled sacs that cells release as a way to communicate with other cells. While exosomes are gaining ground as biologically friendly carriers of therapeutic materials – because there are a lot of them and they don't prompt an immune response – the trick with gene therapy is finding a way to fit those comparatively large genetic instructions inside their tiny bodies on a scale that will have a therapeutic effect. This new method relies on patented technology that prompts donated human cells such as adult stem cells to spit out millions of exosomes that, after being collected and purified, function as nanocarriers containing a drug. When they are injected into the bloodstream, they know exactly where in the body to find their target – even if it's in the brain. And they are gifts that keep on giving, Lee noted: "This is a Mother Nature-induced therapeutic nanoparticle." The study is published today (Dec. 16) in the journal Nature Biomedical Engineering.

In 2017, Lee and colleagues made waves with news of a regenerative medicine discovery called tissue nanotransfection (TNT). The technique uses a nanotechnology-based chip to deliver biological cargo directly into skin, an action that converts adult cells into any cell type of interest for treatment within a patient's own body. By looking further into the mechanism behind TNT's success, scientists in Lee's lab discovered that exosomes were the secret to delivering regenerative goods to tissue far below the skin's surface. The technology was adapted in this study into a technique first author Zhaogang Yang, a former Ohio State postdoctoral researcher now at the University of Texas Southwestern Medical Center, termed cellular nanoporation. The scientists placed about 1 million donated cells (such as mesenchymal cells collected from human fat) on a nano-engineered silicon wafer and used an electrical stimulus to inject synthetic DNA into the donor cells. As a result of this DNA force-feeding, as Lee described it, the cells need to eject unwanted material as part of DNA transcribed messenger RNA and repair holes that have been poked in their membranes. 

"They kill two birds with one stone: They fix the leakage to the cell membrane and dump the garbage out," Lee said. "The garbage bag they throw out is the exosome. What's expelled from the cell is our drug." The electrical stimulation had a bonus effect of a thousand-fold increase of therapeutic genes in a large number of exosomes released by the cells, a sign that the technology is scalable to produce enough nanoparticles for use in humans. Essential to any gene therapy, of course, is knowing what genes need to be delivered to fix a medical problem. For this work, the researchers chose to test the results on glioma brain tumors by delivering a gene called PTEN, a cancer-suppressor gene. Mutations of PTEN that turn off that suppression role can allow cancer cells to grow unchecked. For Lee, founder of Ohio State's Center for Affordable Nanoengineering of Polymeric Biomedical Devices, producing the gene is the easy part. The synthetic DNA force-fed to donor cells is copied into a new molecule consisting of messenger RNA, which contains the instructions needed to produce a specific protein....

Published in Nature Biomedical Engineering (16 December 2019):

https://doi.org/10.1038/s41551-019-0485-1

Katalin Karikó and Drew Weissman laid the groundwork for immunizations that were rolled out during the pandemic at record-breaking speed. This year’s Nobel Prize in Physiology or Medicine has been awarded to biochemist Katalin Karikó and immunologist Drew Weissman for discoveries that enabled the development of mRNA vaccines against COVID-19. The vaccines have been administered more than 13 billion times, saved millions of lives and prevented millions of cases of severe COVID-19, said the Nobel committee. Karikó, who is at Szeged University in Hungary, and Weissman, at the University of Pennsylvania in Philadelphia (UPenn), paved the way for the vaccines’ development by finding a way to deliver genetic material called messenger RNA into cells without triggering an unwanted immune response. They will each receive an equal share of the prize, which totals 11 million Swedish krona (US$1 million). Karikó is the 13th female scientist to win a Nobel Prize in medicine or physiology. She was born in Hungary, and moved to the United States in the 1980s. “Hopefully, this prize will inspire women and immigrants and all of the young ones to persevere and be resilient. That’s what I hope,” she tells Nature.

A new chapter

The COVID-19 vaccines developed by Moderna and the Pfizer–BioNTech collaboration deliver mRNA that instructs cells to create copies of a protein that is found on SARS-CoV-2 virus particles, called the spike protein. This stimulates the body to make antibodies that target the protein, as well as triggering other immune responses. For decades, mRNA vaccines were considered unfeasible because the injection of mRNA into the body triggered an immune reaction that immediately broke down the mRNA. In the mid-2000s, working at UPenn, Karikó and Weissman demonstrated that swapping one type of molecule in mRNA, called uridine, with a similar one called pseudouridine bypasses the cells’ innate immune defences1. “I’m delighted to see them recognized,” says Robin Shattock, a vaccine scientist at Imperial College London, who has worked on mRNA vaccines. “Their contribution was really fundamental in the success of the COVID-19 vaccines, and I think will underlie RNA technology for some time to come.” “They demonstrated that changing the type of the RNA nucleotides within the vaccine altered the way in which cells see it,” said John Tregoning, a vaccine immunologist at Imperial College London, in a press statement for the UK Science Media Centre. “This increased the amount of vaccine protein made following the injection of the RNA, effectively increasing the efficiency of the vaccination: more response for less RNA.” “This discovery has opened a new chapter for medicine,” said Nobel committee member Qiang Pan Hammarström, an immunologist at the Karolinska Institute in Stockholm, at a press conference after the prize announcement. “Investment in long-term basic research is very important.”

doi: https://doi.org/10.1038/d41586-023-03046-x

An experimental personalized mRNA vaccine in combination with the immunotherapy Keytruda reduced the risk of recurrence or death from melanoma in patients who had already had surgery, Moderna and Merck said Tuesday. The randomized trial included 157 patients with stage 3 or stage 4 melanoma who had already had surgery. Some patients received nine doses of the experimental cancer vaccine made by Moderna and the immunotherapy made by Merck every three weeks for about a year, and some received only the immunotherapy. Treatment with the experimental vaccine in combination with the immunotherapy reduced the risk of cancer recurrence or death by 44% compared with the immunotherapy alone, the companies said. The preliminary results of a Phase 2b trial were shared in a news release and have not been peer-reviewed or published. The companies said they will publish the full data in the future and share results at an upcoming conference. The companies said they will initiate a Phase 3 study in melanoma patients next year, and will study additional tumor types.

“Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomized clinical trial in melanoma,” Stéphane Bancel, chief executive officer for Moderna, said in a news release. Moderna is the maker of one of the mRNA Covid-19 vaccines used in the United States. Moderna and Merck said serious treatment-related adverse events occurred in 14.4% of patients who received the vaccine and immunotherapy in the trial, and in 10% of patients who received only the immunotherapy. Keytruda has some known risks for serious side effects, the companies said. Moderna’s experimental cancer vaccine, mRNA-4157/V940, is designed to prime patients’ immune system to generate a response to their specific tumors. Merck’s Keytruda, which is already used in the treatment of melanoma, stimulates the immune system to attack tumors. According to the American Cancer Society, melanoma accounts for about 1% of all skin cancers, but it causes a majority of skin cancer deaths. It estimates that in 2022, about 100,000 new melanomas will be diagnosed, and more than 7,600 people will die from melanoma.

Press release (Dec. 13, 2022):

https://investors.modernatx.com/news/news-details/2022/Moderna-and-Merck-Announce-mRNA-4157V940-an-Investigational-Personalized-mRNA-Cancer-Vaccine-in-Combination-with-KEYTRUDAR-pembrolizumab-Met-Primary-Efficacy-Endpoint-in-Phase-2b-KEYNOTE-942-Trial/default.aspx 

With as much turmoil and negativity as the COVID-19 pandemic has supplied, there may be a silver lining when it comes to a new vaccine study for those suffering with HIV. The first study participant has been enrolled in a new Phase 1 clinical trial using the messenger ribonucleic acid, or mRNA, vaccine technology developed by Moderna to evaluate the safety and immune responses of three different experimental vaccines against HIV. This randomized, open-label trial represents one of the first clinical studies of the use of mRNA vaccine technology against HIV. The University of Alabama at Birmingham enrolled the trial’s second participant and has enrolled several others since.

Paul Goepfert, M.D., director of the Alabama Vaccine Research Clinic in the Marnix E. Heersink School of Medicine, says the emergence of mRNA vaccines to combat COVID-19 certainly helped move this mRNA HIV vaccine trial along. “Despite tremendous advancements in treatment and prevention of HIV, we still do not have an effective vaccine and thousands of Americans continue to be infected every year,” Goepfert said. “mRNA technology enables a much more rapid development of vaccines that was not previously possible. This new technology will certainly decrease the time it will take to develop an effective HIV vaccine.” The study, HVTN 302, will enroll up to 108 HIV-negative adults. The primary study hypothesis is that the mRNA vaccines will be safe and well-tolerated among HIV-negative people and will elicit neutralizing antibodies.

The experimental vaccines carry mRNA, a piece of genetic code, delivered with instructions for making proteins in the same way that the mRNA vaccines against COVID-19 instruct the body’s cells to make the SARS-CoV-2 spike protein. These instructions show human muscle cells how to make small portions of proteins that resemble parts of HIV but are not the actual virus. People cannot contract HIV from the vaccines. Once immune cells have used the instructions, the mRNA is quickly broken down, and does not stay in the body. The investigational vaccines are not expected to provide protection from HIV infection, yet the knowledge gained from this study will aid in the future development of an HIV vaccine regimen. Researchers hope to learn whether the immune system will respond to the experimental vaccines by making antibodies and T cells that could fight HIV if a person is ever exposed to the virus in the future. The trial will also clarify whether the immune response to an mRNA vaccine is equal to or better than the response to a protein-based vaccine, while helping define the potentials of using mRNA to increase the pace of developing an HIV vaccine. UAB is one of 10 sites nationwide, and the sole site in the South, to enroll participants. At UAB, Goepfert holds the Edward W. Hook, III, M.D., Endowed Professorship in Infectious Diseases. 

Vaccine makers are betting that the mRNA technology powering two successful Covid vaccines will help curb the tragic global death toll from the flu.  As the world grapples with Covid-19, influenza isn’t getting much attention these days. But the flu’s global impact is staggering: three million to five million cases of severe illness every year, and up to 650,000 deaths. Every few decades, a new flu strain spills over from animals and leads to a pandemic. The deadly toll of influenza is all the more striking when you consider that we have had vaccines to fight it for eight decades. But they remain mediocre. A flu shot is good for only one flu season, and its effectiveness typically reaches somewhere between 40 and 60 percent. In some years it’s as low as 10 percent. But a new generation of highly effective flu vaccines may emerge in the next few years, based on the same mRNA technology that has protected hundreds of millions of people against Covid-19. While traditional influenza vaccines are grown for months in chicken eggs, mRNA vaccines are manufactured relatively quickly from scratch. In theory, their faster production may make them better matched to each season’s flu strains. And when they’re injected into people, they may provoke a stronger immune response than traditional flu vaccines do.

Two companies — Moderna, the Massachusetts biotech company that produced one of the authorized mRNA vaccines for Covid-19, and Sanofi, a French vaccine maker — began trials for mRNA flu vaccines this summer. Pfizer and BioNTech, the companies that produced the other mRNA Covid-19 vaccine, started their own flu trial last month. And Seqirus, a vaccine producer based in England, is planning to test another mRNA vaccine for the flu early next year.  No one can say for sure how well any of these four seasonal flu vaccines will turn out, but many experts are optimistic. And further down the line, mRNA technology may be tailored to make vaccines that work for years against a wide range of influenza strains. “I am beyond excited for the future of flu vaccination,” said Jenna Bartley, an immunologist at the University of Connecticut. No one can say for sure how well any of these four seasonal flu vaccines will turn out, but many experts are optimistic. And further down the line, mRNA technology may be tailored to make vaccines that work for years against a wide range of influenza strains. “I am beyond excited for the future of flu vaccination,” said Jenna Bartley, an immunologist at the University of Connecticut.

Novel treatment using messenger RNA sharply cuts production of mutant liver protein, although it’s too early to show patients with rare condition benefit. The gene editor CRISPR excels at fixing disease mutations in lab-grown cells. But using CRISPR to treat most people with genetic disorders requires clearing an enormous hurdle: getting the molecular scissors into the body and having it slice DNA in the tissues where it’s needed. Now, in a medical first, researchers have injected a CRISPR drug into the blood of people born with a disease that causes fatal nerve and heart disease and shown that in three of them it nearly shut off production of toxic protein by their livers.  Although it’s too soon to know whether the CRISPR treatment will ease the symptoms of the disease, known as transthyretin amyloidosis, the preliminary data reported today are generating excitement about what could be a one-time, lifelong treatment. “These are stunning results,” says gene editing researcher and cardiologist Kiran Musunuru of the University of Pennsylvania, who was not involved in the trial. “It exceeds all my expectations.” The work also marks a milestone for the race to develop treatments based on messenger RNA (mRNA), the protein-building instructions naturally made by cells. Synthetic mRNAs power two COVID-19 vaccines being given to millions of people to fight the coronavirus pandemic, and many companies are working on other mRNA vaccines and drugs. The new treatment, which includes an mRNA encoding one of CRISPR’s two components, “begins the convergence of the fields of CRISPR and mRNA,” says cardiovascular researcher Kenneth Chien of the Karolinska Institute, a co-founder of Moderna, which makes one of the COVID-19 vaccines and is also developing mRNA drugs. The CRISPR clinical trial aims to deactivate a mutated gene that causes liver cells to churn out misfolded forms of a protein called transthyretin (TTR), which build up on nerves and the heart and lead to pain, numbness, and heart disease. The resulting condition is relatively rare, and an approved drug, patisiran, can stabilize it. But researchers at veteran biotech Regeneron Pharmaceuticals and startup Intellia Therapeutics saw it as a good proof of principle for the injectable CRISPR treatment they were developing. 

Last year, researchers used CRISPR to turn on a fetal form of hemoglobin to correct sickle cell disease or a related disease in several people. The treatment required removing a patient’s diseased blood stem cells, modifying them with CRISPR in a dish, and then infusing them back into the body. A trial testing a direct injection of a virus encoding CRISPR’s components into the eye to treat a condition that causes blindness is also underway. But treating most other diseases means somehow injecting CRISPR’s components, or genetic instructions for them, into the blood and having the therapy target an organ or tissue—a huge challenge, but potentially easier in the liver because it sops up foreign particles. In the CRISPR trial, four men and two women with transthyretin amyloidosis between ages 46 and 64 were injected with a lipid particle carrying two different RNAs: an mRNA encoding the protein Cas, the CRISPR component that snips DNA, and a guide RNA to direct it to the gene for TTR. After Cas makes its cut, the cell’s DNA repair machinery heals the break, but imperfectly, knocking out the activity of the gene. After 28 days, three men given the higher of two doses of the treatment had an 80% to 96% drop in TTR levels, on par or better than the average of 81% with patisiran, the team reports today in The New England Journal of Medicine. “The data are extremely encouraging,” says trial leader Julian Gillmore of University College London, who also presented the study today at the online annual meeting of the Peripheral Nerve Society. “It could be potentially the first curative treatment for this hereditary disabling and life-threatening disease,” says neurologist David Adams of the University of Paris-Saclay, who led trials for patisiran. (That drug is a kind of RNA that silences TTR's production temporarily, meaning it must be injected on a regular basis.)

It may take months for patients receiving the CRISPR treatment to see their symptoms lessen, but they reported few short-term side effects. Problems could surface over time: CRISPR could potentially make cuts in the wrong DNA location (and in non-liver cells), triggering cancer or other problems. But the lipid-encased mRNA approach is potentially safer than using viruses to ferry genetic instruction for encoding an editing protein and guide RNA into cells, a tried-and-true approach others are pursuing for systemic treatments. Those genes can persist in cells, continuing to make the gene editor long after it has done its job. In contrast, “The beauty of mRNA is that it is gone afterwards,” Chien says. The study paves the way for treating other liver diseases with CRISPR, either by knocking out a gene or—more challenging—modifying it with the help of a DNA template. The latter approach could also be used to turn the liver into a factory for making an enzyme needed elsewhere in body. Jennifer Doudna of the University of California, Berkeley, who shared a Nobel Prize last year for discovering CRISPR and co-founded Intellia, sees even bigger prospects. The new work, she says, is “a critical first step in being able to inactivate, repair, or replace any gene that causes disease, anywhere in the body.”

See also NEJM (June 26, 2021):

https://www.nejm.org/doi/full/10.1056/NEJMoa2107454 

Researchers at the University of Duke found mRNA-based vaccines, such as Pfizer and Moderna, induce antibodies that may help fight against coronavirus variants.  The Pfizer and Moderna vaccines are not only effective against COVID-19, but may also help prevent future pandemics. Researchers at Duke University came to this concluding after testing mRNA-based vaccines similar to the jabs used on lab monkeys. According to their findings, which were published in Nature this week, these variety of vaccines induced “broadly neutralizing” antibodies that appeared to protect against Sars-CoV-2—the infection that causes COVID-19—as well as potential variants of coronavirus that could jump from animal to human.  The findings may offer the public a sense of relief as many experts and epidemiologists say there’s a strong chance another pandemic will occur. In an effort to help prevent another outbreak, the team of Duke University researchers developed a pan-coronavirus vaccine that is protein-based rather than mRNA-based. The vaccine was tested on lab animals and showed promising results in fighting the original COVID-19 strain and other variants. Researchers said the vaccine also appeared to stop the virus from replicating in the lungs and nose, which could drastically reduce rates of transmission.

“We began this work last spring with the understanding that, like all viruses, mutations would occur in the SARS-CoV-2 virus,” the study’s senior author Barton F. Haynes, director of the Duke Human Vaccine Institute, said in a press release. “The mRNA vaccines were already under development, so we were looking for ways to sustain their efficacy once those variants appeared. This approach not only provided protection against SARS-CoV-2, but the antibodies induced by the vaccine also neutralized variants of concern that originated in the United Kingdom, South Africa and Brazil. And the induced antibodies reacted with quite a large panel of coronaviruses.”  Dr. Anthony Fauci, the nation’s leading expert in infectious diseases, expressed optimism about Duke’s pan-coronavirus vaccine during a Thursday press conference, saying the next step was to get approval for human trials. “We always have to have a caveat when you’re dealing in a nonhuman primate,” he said, “nonetheless, this is an extremely important proof of concept that we will be aggressively pursuing as we get into the development of human trials,” Fauci said.

Cited study published in Nature (May 10, 2021):

https://doi.org/10.1038/s41586-021-03594-0 

Moderna said Monday that its coronavirus vaccine candidate is 94.5% effective in fighting the virus, per an initial analysis released by the company.

Why it matters: The Moderna vaccine — alongside Pfizer's similarly effective candidate — provides another dash of hope that the pandemic currently raging across the world could be tamed by next year.

The state of play: Moderna's study, done in collaboration with the National Institute of Health, looked at 30,000 participants — with half receiving a placebo.

• In 95 cases of COVID-19 that developed among participants, 90 were taking the placebo.
• Of the 11 people who contracted "severe" COVID-19 infections, all were taking a placebo.
• Moderna reports there are no significant safety concerns so far.
• The company also said that the vaccine could be stored at refrigerator temperatures for up to a month — compared to Pfizer's vaccine candidate, which requires ultra-cold conditions.

What they're saying: "It’s extremely good news. If you look at the data, the numbers speak for themselves," said Dr. Anthony Fauci, per the Washington Post.

• "I describe myself as a realist, but I’m fundamentally a cautious optimist. I felt we’d likely get something less than this. … I said certainly a 90-plus-percent effective vaccine is possible, but I wasn’t counting on it."

The big picture: The Moderna vaccine was part of the federal government's Operation Warp Speed acceleration project, and the company received about $2.5 billion to back its research and development.

• Pfizer, on the other hand, funded its own vaccine research but did commit to an Operation Warp Speed deal to speed potential distribution.

Worth noting: Like Pfizer's announcement last week, Moderna's details on its vaccine candidate came in the form of a press release.

• The data has not been peer-reviewed and its effectiveness could change as the study progresses, but Moderna says they plan to submit to a peer-reviewed publication when the study is complete.
• Pfizer CEO Albert Bourla said that his company had avoided such specificity about effectiveness given that the numbers could continue changing as its trial continues.

Moderna's press release (Nov. 16, 2020):

https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy

Moderna, a biotech advancing one of the leading COVID-19 vaccine candidates, has faced questions for several months over its patents and intellectual property. Responding to investor questions, the company now says it won't enforce its vaccine patents against other companies during the pandemic. In a Wall Street Journal interview, company President Stephen Hoge said Moderna is “quite studiously not asserting infringement.” Without naming names, the biotech says other COVID-19 vaccines in development might be using Moderna-patented technology. “We’re not interested in using that IP to decrease the number of vaccines available in a pandemic,” Hoge told the WSJ. Further, the company is open to licensing its technology after the pandemic. Moderna made the pledge in response to investor questions around its patents, Hoge told the newspaper. Moderna says it has spent billions of dollars on mRNA research over the years, but its patents have come under scrutiny on several occasions during the pandemic. Over the summer, the company lost an attempt to invalidate a patent held by Arbutus Biopharma, prompting analysts to wonder how the decision might affect Moderna's COVID-19 work. At the time, a patent lawyer told Reuters the decision increased the pressure on Moderna to seek a sublicense on technology covered by the patent.  

Still, it isn’t completely clear whether Moderna’s potential launch would be affected by Arbutus’ patent. Moderna has a “broad [intellectual property] portfolio covering our development and commercialization of mRNA vaccine and therapeutic programs,” the company said in its latest quarterly filing with the Securities and Exchange Commission. But there are risks. Messenger RNA is a new field, and various patent applications are being processed around the world. There’s “uncertainty about which patents will issue, and, if they do, as to when, to whom, and with what claims,” the company noted in the filing. It’s “possible that one or more organizations will hold patent rights to which we may need a license, or hold patent rights which could be asserted against us," Moderna added. Pfizer and BioNTech are advancing the other lead mRNA vaccine candidate, but a Pfizer spokeswoman told the WSJ that BioNTech holds the patents for that project.

For its part, Public Citizen has argued the U.S. government has partial rights to Moderna coronavirus vaccine patents. The company’s latest move “presumably is designed to help the corporation avoid costly patent litigation,” Peter Maybarduk, the group’s access to medicines director, said in a statement.   Public Citizen’s research has found that U.S. taxpayers will end up having to pay twice for the vaccine—first through initial research and then through the procurement of doses. Further, the U.S. government may have some rights to key patents, Public Citizen concluded in an analysis of documents obtained by Axios. 

The study showed that vaccinated volunteers made more neutralizing antibodies than have been seen in most patients who have recovered from Covid-19. Moderna's Covid-19 vaccine led patients to produce antibodies that can neutralize the novel coronavirus that causes the disease, though it caused minor side effects in many patients, according to the first published data from an early-stage trial of the experimental shot. The results were published Tuesday in the New England Journal of Medicine. Moderna had previously released some results in a press release, but many experts said they were not sufficient to draw many conclusions. Even now, many are withholding judgment.

“It certainly is a good beginning,” said Betty Diamond, director at the Feinstein Institutes for Medical Research, who was not involved in the trial. “There are certainly lots of things we don’t know yet right now.” The study, which was run by the National Institutes of Health, showed that volunteers who received the vaccine made more neutralizing antibodies than have been seen in most patients who have recovered from Covid-19. But a second injection, four weeks after the first, was required before the vaccine produced a dramatic immune response. “The hallmark of a vaccine is one that can actually mimic natural infection and induce the kind of response that you would get with natural infection. And it looks like, at least in this limited, small number of individuals, that is exactly what’s happening,” said Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, the NIH branch that conducted the trial. “The data really look quite good,” he added. “There were no serious adverse events.”

The data roughly mirror the results from a similar vaccine being produced by Pfizer and BioNTech, which were released July 1. Moderna posted a listing on clinicaltrials.gov, a government registry, that says it will start a Phase 3 study in 30,000 patients on July 27. Pfizer and BioNTech said they plan to start their own large study by the end of the month. There are 23 vaccines in human clinical trials against the virus, SARS-CoV-2, according to the World Health Organization, with more set to begin testing soon. In a statement, Moderna CEO Stéphane Bancel called the data “encouraging,” saying they “represent an important step forward” in the development of the vaccine, called mRNA-1273. “We are committed to advancing the clinical development of mRNA-1273 as quickly and safely as possible while investing to scale up manufacturing so that we can help address this global health emergency,” Bancel said....

Original study available at New England J. Medicine (July 14, 2020):

https://doi.org/10.1056/NEJMoa2022483

Phase 2 study expected to enroll 600 participants Finalizing protocol for Phase 3 study, expected to begin in July 2020 Moderna, Inc. , (Nasdaq: MRNA) a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines otday announced that the first participants in each age cohort have been dosed in the Company’s Phase 2 study of its mRNA vaccine candidate (mRNA-1273) against the novel coronavirus (SARS-CoV-2).

This Phase 2 study, being conducted by Moderna under its own Investigational New Drug (IND) application, will evaluate the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart. The Company intends to enroll 600 healthy participants across two cohorts of adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300). Each participant will be assigned to receive placebo, a 50 μg or a 100 μg dose at both vaccinations. Participants will be followed through 12 months after the second vaccination. Given the 25 μg and 100 μg dose levels in the Phase 1 study showed neutralizing antibody titers at or above convalescent sera and were generally well tolerated, the Company has decided not to pursue the 250 μg dose level in the Phase 2 study. On May 6, the U.S. Food and Drug Administration (FDA) completed its review of the Company’s Investigational New Drug (IND) application for mRNA-1273 and on May 12, the FDA granted it Fast Track designation. On May 18, Moderna announced initial data from the Phase 1 study of mRNA-1273 led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The NIH will be submitting the Phase 1 data to a peer-reviewed clinical publication. Moderna anticipates collaborating with NIAID to implement the Phase 3 study. The dose for the Phase 3 study is expected to be between 25 µg and 100 µg and expects Phase 3 trial initiation in July, subject to finalization of the clinical trial protocol.

Funding from the Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services (HHS), supported the planning for these studies and will also support the late-stage clinical development programs, as well as the scale-up of mRNA-1273 manufacturing both at the Company’s facilities and that of its strategic collaborator, Lonza Ltd. A summary of the company’s work to date on SARS-CoV-2 can be found here.

The first human trials of a coronavirus vaccine developed by researchers at the University of Oxford will start today in the U.K. Making the announcement at a recent press briefing, U.K. government Health Secretary Matt Hancock pledged £20 million in government funding to support Oxford University’s ChAdOx1 nCoV-19 coronavirus vaccine program, and another £22.5 million to fund Phase II testing of a coronavirus vaccine in development by Imperial College London, which is projected to start human testing in June. The Imperial College London funding will also be used to help prepare for Phase III studies. “We will throw everything we’ve got at developing a vaccine,” Hancock added. “The U.K. is at the forefront of the global effort … and for all of the efforts around the world, two of the leading vaccine developments are taking place here at home, at Oxford and Imperial.”

The start of human testing in the U.K. coincides with Germany’s regulator, the Paul-Ehrlich-Institut, giving German biotech BioNTech and partner Pfizer the green light to start the first coronavirus vaccine clinical trial in the country. “This is the fifth authorized clinical trial worldwide in which a preventive specific COVID-19 vaccine candidate is tested in humans,” the Federal Institute for Vaccines and Biomedicines said. The Phase I/II study will evaluate the BNT162 vaccine program. Clinical trials are also expected to start in the United States upon regulatory approval, which is anticipated shortly, Pfizer said. The first part of the clinical study in Germany will test variants of the vaccine in 200 healthy volunteers aged 18–55 years. The second part of the study will be expanded to include volunteers who are at an increased risk of infection or increased risk of serious COVID-19 disease.