How Does an mRNA Vaccine Work?

The COVID-19 pandemic has brought unusual attention to everything from handwashing to polymerase chain reaction (PCR) tests. As we move into the later stages of this pandemic, though, a different scientific concept has dominated the national conversation: vaccines. The study of the human immune system and how vaccines influence it is complex and sometimes counterintuitive, and the deployment of a new method for immunization based on mRNA has made it all the more confusing.

The two vaccines that have received Emergency Use Authorizations (EUAs) from the Food and Drug Administration are both mRNA vaccines. And since they’re our only hope for ending this pandemic, it’s crucial to understand how they work—and why you should get one.

Vaccines come in a few main forms, but they share the same central goal: equip our immune systems with the tools to handily defeat a pathogen we might encounter in the future. Think of it like a practice round before your body sees the real thing.

The exact way our bodies develop this preemptive immunity depends on the kind of vaccine we’re given. Live-attenuated vaccines provide our cells with a weakened version of a pathogen; protein subunit vaccines give just one part of a bad guy, so immune cells know how to recognize that part of a virus or bacterium. But mRNA (short for messenger RNA) vaccines actually provide our cells with the instructions for making a protein from the pathogen, in essence creating their own practice dummy. Our own cells produce the viral protein specific to, say, SARS-CoV-2, and then our immune system learns to recognize the proteins.

Source: https://www.popsci.com/

Immune System Killer Cells Controlled By Circadian Rhythms

An analysis of an exhaustive dataset on cells essential to the mammalian immune system shows that our ability to fight disease may rely more heavily on daily circadian cycles than previously assumed.

Malfunctions in , the process that keeps our bodies in tune with the day/night cycles, are increasingly associated with diabetes, cancer, Alzheimer’s, and many other diseases. An investigation published today in Genome Research shows that the activity of macrophagescells within us that seek and destroy intruders like bacteria—may time daily changes in their responses to pathogens and stress through the circadian control of metabolism. In this study, Jennifer Hurley, the Richard Baruch M.D. Career Development Assistant Professor of Biological Sciences at Rensselaer Polytechnic Institute and senior author on this study, and her team investigated how the levels of RNA and proteins in macrophages change over two days.

We have shown there is an incredible amount of circadian timing of macrophage behavior, but the clock is timing macrophages in unexpected ways” said Hurley.

The circadian system is comprised of a set of core clock proteins that anticipate the day/night cycle by causing daily oscillations in levels of enzymes and hormones, and ultimately affecting physiological parameters such as body temperature and the immune response. This molecular clock marks time through a self-regulating cycle of  production and decay. The “positive” element proteins of the clock trigger production of the “negative” element proteins, which in turn block production of positive element proteins until the negative element proteins decay, thus creating a negative feedback cycle that occurs once every 24 hours.

Positive element proteins also regulate fluctuations in a substantial number of gene products, known as messenger RNA or mRNA. Genetic instructions are transcribed from DNA to mRNA, which are then used as a recipe for assembling proteins, the functional building blocks of the cell. It has long been assumed that the levels of each subsequent step could be predicted from the previous. If that were the case, oscillating mRNA would correspond with oscillating levels of cellular proteins, and therefore, if one could track mRNA, they would know what proteins the circadian clock controlled in the cell.

However, this investigation showed that this paradigm may not always be true. The analysis of the macrophage dataset revealed that there was a substantial mismatch between the proteins and mRNAs that are controlled by the circadian clock. This data paralleled research published in Cell Systems in 2018 by the Hurley lab, showing that about 40% of oscillating proteins in the fungus and circadian model system, Neurospora crassa, had no corresponding oscillating mRNA.

But the scale of the difference in macrophages really surprised us,” Hurley said. “Eighty percent of the proteins that oscillate don’t have associated oscillating mRNA in macrophages. That means we were really missing how the clock was timing immunity.”

Source: https://medicalxpress.com/

CRISPR Treatment Destroys Cancer Cells

Researchers at Tel Aviv University (TAU) have demonstrated that the CRISPR/Cas9 system is very effective in treating metastatic cancers, a significant step on the way to finding a cure for cancer. The researchers developed a novel lipid nanoparticle-based delivery system that specifically targets cancer cells and destroys them by genetic manipulation. The system, called CRISPR-LNPs, carries a genetic messenger (messenger RNA), which encodes for the CRISPR enzyme Cas9 that acts as molecular scissors that cut the cells’ DNA.

The revolutionary work was conducted in the laboratory of Prof. Dan Peer at TAU. Dr. Daniel Rosenblum led the research together with Ph.D. student Anna Gutkin and colleagues.

To examine the feasibility of using the technology to treat cancer, Prof. Peer and his team chose two of the deadliest cancers: glioblastoma and metastatic ovarian cancer. Glioblastoma is the most aggressive type of brain cancer, with a life expectancy of 15 months after diagnosis and a five-year survival rate of only 3%. The researchers demonstrated that a single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors, improving their overall survival rate by about 30%. Ovarian cancer is a major cause of death among women and the most lethal cancer of the female reproductive system. Most patients are diagnosed at an advanced stage of the disease when metastases have already spread throughout the body. Despite progress in recent years, only a third of the patients survive this disease. Treatment with CRISPR-LNPs in a metastatic ovarian cancer mice model increased their overall survival rate by 80%.

The CRISPR genome editing technology, capable of identifying and altering any genetic segment, has revolutionized our ability to disrupt, repair or even replace genes in a personalized manner,” said Prof. Peer. “Despite its extensive use in research, clinical implementation is still in its infancy because an effective delivery system is needed to safely and accurately deliver the CRISPR to its target cells. The delivery system we developed targets the DNA responsible for the cancer cells’ survival. This is an innovative treatment for aggressive cancers that have no effective treatments today.

This is the first study in the world to prove that the CRISPR genome editing system can be used to treat cancer effectively in a living animal,” explained Prof. Peer. “It must be emphasized that this is not chemotherapy. There are no side effects, and a cancer cell treated in this way will never become active again. The molecular scissors of Cas9 cut the cancer cell’s DNA, thereby neutralizing it and permanently preventing replication.”

The results of the groundbreaking study were published in November 2020 in Science Advances.

Source: https://english.tau.ac.il/
AND
 https://www.eurekalert.org/

Pfizer Says Its COVID-19 Vaccine Is 95% Effective

Pfizer and BioNTech said Wednesday that a final data analysis found their coronavirus vaccine was 95% effective in preventing COVID-19 and, in addition, appeared to fend off severe disease.

Vaccine, called BNT162b2, was highly effective against the virus 28 days after the first dose, and its effectiveness was consistent across all ages, races and ethnicities, the drugmakers said. Additionally, the elderly, who are seen as at high risk of severe illness from COVID-19, saw vaccine effectiveness of more than 94%, they added.

The final analysis underlines the results of the positive interim efficacy analysis announced on November 9,” BioNTech CEO Ugur Sahin said in a statement. “The data indicates that our vaccine … is able to induce a high rate of protection against COVID-19 only 29 days after the first dose. In addition, the vaccine was observed to be well-tolerated in all age groups with mostly mild to moderate side effects, which may be due in part to the relatively low dose.”

The vaccine also appeared to prevent severe disease in volunteers. There were 10 cases of severe cases of COVID-19 observed in the phase three trial, with nine of the cases occurring in the placebo group, the companies said. There were also no “serious” safety concerns, they said, with most adverse events resolving shortly after vaccination. The company’s shares jumped 3% in premarket trading.

The final analysis evaluated 170 confirmed COVID-19 infections among the late-stage trial’s more than 43,000 participants. The companies said 162 cases of COVID-19 were observed in the placebo group versus eight cases observed in the group that received its two-dose vaccine. That resulted in an estimated vaccine efficacy of 95%, they said.

The news comes more than a week after the companies announced that their vaccine was more than 90% effective and two days after Moderna said preliminary phase three trial data showed its vaccine was 94.5%. Both vaccines use messenger RNA, or mRNA, technology. It’s a new approach to vaccines that uses genetic material to provoke an immune response.

A safe and effective vaccine is seen by investors and policymakers as a solution to get the global economy back on track after the pandemic wreaked havoc on nearly every country across the globe and upended businesses. The virus continues to spread rapidly, with more than 55.6 million cases worldwide and at least 1.33 million deaths as of Wednesday, according to data compiled by Johns Hopkins University.

Pfizer and BioNTech‘s initial results on Nov. 9 were based on the first interim efficacy analysis conducted by an external and independent Data Monitoring Committee from the phase three clinical trial. The independent group of experts oversees U.S. clinical trials to ensure the safety of participants. Medical experts note it remains unclear how long the vaccines will provide immunity and whether or how often people may need periodic booster shots.

These vaccines are going to be approved and then rolled out with basically a few months’ worth of data. You’re not going to do a two-year study to see whether it’s effective for two years with more than 200,000 people dying this year” in the U.S., Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, said in a recent interview.

Pfizer said it plans to submit an application for emergency use authorization to the Food and Drug Administrationwithin days.” Pfizer CEO Albert Bourla said at Tuesday’s New York Times Dealbook conference that the company had accumulated enough safety data needed to submit the vaccine for review.

The companies reiterated that they expect to produce up to 50 million doses this year and up to 1.3 billion doses in 2021. They also said they are “confident” in their ability to distribute the vaccine, which requires a storage temperature of minus 94 degrees Fahrenheit. By comparison, Moderna‘s vaccine can be stored for up to six months at negative 4 degrees Fahrenheit.

Source: https://www.nbcdfw.com/