BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: Spike Proteins

Optimus Prime, Megatron, Proteins? The New Transformer Vaccine Candidate!

Amid the global outbreak of COVID-19, with no end in sight after nearly two years, the future wellbeing of humans is in danger. Coughs, fevers, and shortness of breath have lent way to millions of deaths across the globe. As thousands of researchers relentlessly work to find solutions to this virus, multiple vaccine candidates have emerged. Specifically, in the United States, millions of Americans have received doses of the Pfizer-BioNTech, Moderna, and Johnson & Johnson’s Janssen vaccines. However, scientists at Scripps Research recently recognized a new, self-assembling COVID-19 vaccine as a potentially more efficient and effective way to fight this worldwide battle.

 

Primarily, it is critical to understand how vaccines function as they help protect the immune system. The COVID-19 vaccines currently in effect are mRNA-based; in other words, the messenger RNA signals one’s body to produce a harmless viral protein that resembles the structure of a spike protein. The body, with the help of T-Helper cells, recognizes this structure as a foreign invader as B cells bind to and identify the antigen. The T-Helper cells will then signal these B cells to form B-Plasma cells and B-Memory cells. When getting the vaccine, the B-Memory cells are especially important as they prevent reinfection. This is a process known as adaptive immunity. Here, in the event of future infection with the spike-protein COVID-19, the memory cells would help carry out the same response more quickly and efficiently. Essentially, this process acts as the body’s training in case of any future infections.

 

While the Scripps Research COVID-19 vaccine would evoke a similar immune response to that described above, it differs from other candidates in how it assembles in the human body; this new vaccine would be comprised of proteins that are able to self-assemble. On their own, these nanoparticle proteins would transform into a sphere protein structure surrounded by smaller proteins, mimicking the coronavirus’s shape. Here, the self-assembled spike proteins are more sturdy and stable than in an mRNA-produced structure. Thus, it more accurately prepares the body for future infection with COVID-19. In fact, multiple tests found that mice who were given the experimental vaccine were able to fight off not only SARS-CoV-2 but also SARS-CoV1 along with the alpha, beta and gamma variants.

 

Nonetheless, influencing the public to get a newer vaccine instead of the well-trusted vaccines already in production requires proof of the candidate’s benefits. Primarily, as mentioned, early results find that this new candidate would perform well with many different strains of COVID-19. Additionally, researchers assert that this vaccine would be relatively simple to produce on a mass scale. Lastly, scientists found that this vaccine may well be more protective and long-lasting than current vaccine candidates. Although the process of vaccine approval is lengthy and often difficult, I am hopeful for the future of the Scripps Research vaccine if it is put into production. Moreover, I believe that such experimentation with self-assembling nanoparticle proteins transcends the current pandemic. The benefits of this field present a wide array of opportunities, and I look forward to seeing what its future may hold.

 

What do you think? Are these transformer-like self-assembling particles a gateway to the future of medicine or an unnecessary distraction from effective treatments already in circulation?

Changing Composition of SARS-CoV-2/Understanding the Alpha Variant in England

Since its emergence in the Fall of 2020, the original SARS-CoV-2 variant of concern (VOC) rapidly became the dominant lineage across much of Europe. Although, simultaneously, several other variants of concern were identified globally. Like B.1.1.7 or the Alpha Variant (first mutation of SARS-CoV-2 found to be more transmissible), these VOCs possess mutations thought to create only partial immunity.

Researchers are understanding when and how these additional VOCs pose a threat in settings where B.1.1.7 is currently dominant. This is where scientists in the UK examined trends in the prevalence of non-B.1.1.7 lineages in London and other English regions using passive-case detection PCR data, cross-sectional community infection surveys, genomic surveillance, and wastewater monitoring. The study period spanned from January 31st of 2021 to May 15th of 2021.

Through this data, the percentage of non-B.1.1.7 variants has been increasing since late March 2021. This increase was initially driven by a variety of lineages with immune escape. From mid-April, B.1.617.2 (WHO label of Delta) spread rapidly, becoming the dominant variant in England by late May, similarly to the Alpha Variant.

Shown by many mutations in the spike protein receptor (RBD), studies suggest B.1.1.7 is 50–80% more transmissible with greater severity than previously circulating Covid Variants. B.1.1.7 rose rapidly, from near 0% to over 50% in under two months, and soon made up greater than 98% of sequenced samples in England. Its rapid spread necessitated a third lockdown in England during last January. Subsequent spread in Europe and North America has highlighted the threat this variant poses to a continued alteration of the Coronavirus.

The 69–70 deletion in B.1.1.7′s Spike gene causes PCR tests to return negative results for that gene target which is a major problem when identifying and testing for Covid. One of the most important changes in lineage of B.1.1.7 seems to be a spike protein substitution of N501Y, a change from asparagine to tyrosine in amino-acid position, that enhances transmission. These alterations can change antibody recognition while also affecting ACE2’s (receptor protein) binding specificity which can then lead to the virus becoming more infectious. We are seeing a pattern of the same type of mutation in Covid consistently.

An example of a similar mutation that has been recent is the new Omicron variant out of South Africa. Omicron is similar in which their has been a specific change in the spike protein where antibody recognition is limited and it is highly transmissible between any living organism. Our class has understood and studied the importance of our body being able to identify and create an antibody for the specific antigen being displayed by a pathogen.  These mutations within the spike protein allow another immune response to happen which a different antibody has to be created to mark the different antigen being displayed. Unfortunately, this will be a continuing problem without vaccine mandates since it gives the virus more time to mutate where outbreaks like in South Africa will continue to transpire around the world.

How Killer T Cells Could Increase Immunity Against New COVID Variants.

In recent news, there are concerns about the newly discovered COVID variant named Omicron. Preliminary evidence suggests an increased risk of reinfection with this variant, as compared to other variants of concern. Scientists are hopeful that T cells could provide some immunity to COVID-19, even if antibodies become less effective at fighting the disease.

Along with antibodies, the human body’s immune system produces a plethora of T cells which target viruses. Helper T cell’s stimulate killer T cells, macrophages, and B cells to make immune responses. T cells do not prevent infection because they kick into action only after a virus has infiltrated the body. But, they are important for clearing an infection that has already started. If killer T cell’s are able to kill virus-infected cells before they are able to spread to from the upper respiratory tract, it will affect how you feel and will be the difference between a mild infection and a severe one.

Studies by Sette and his colleagues have shown that people who have been infected with SARS-CoV-2 typically generate T cells that target at least 15–20 different fragments of coronavirus proteins. But, the protein particles that are targeted vary from person to person. This means that a variety of T cells will be generated, making it difficult for the virus to mutate in attempt to escape cell recognition. Research suggests that most T-cell responses to COVID variations or previous infection do not target regions that were mutated in recently discovered variants. If T Cells remain active within your immune system against specific variants, they might protect against severe diseases.

Ultimately, in my opinion, this is extremely important since researchers have been analyzing clinical-trial data for several coronavirus vaccines in attempt to find clues as to whether their effectiveness fades in the face of new emerging COVID variants such as Omicron. As of now, coronavirus vaccine developers are already looking at ways to develop next-generation vaccines that stimulate T cells more effectively. Antibodies only detect proteins outside cells, and many coronavirus vaccines target spike proteins, located on the surface of the virus. Since spike proteins are liable to change, it may be prone to mutating and raising the risk that emerging variants will be able to evade antibody detection. T cells, on the other hand, can target viral proteins located inside infected cells, and some of those proteins are very stable. This raises the possibility of designing vaccines against proteins that mutate less frequently than spike proteins, and incorporating targets from multiple proteins into one vaccine.

Biotechnology firm Gritstone Oncology of Emeryville, California, is designing an experimental vaccine that incorporates the genetic code for fragments of several coronavirus proteins known to elicit T-cell responses, as well as for the full spike protein, to ensure that antibody responses are robust. Clinical trials are due to start in the first quarter of next year. If approved, this vaccine could revolutionize how we approach the creation and experimentation of COVID vaccines in the future.

Dr. Kizzmekia Corbett, Vaccine Visionary

Despite the recently-approved Moderna Covid-19 vaccine’s place at the forefront of many STEM-related discussions, the fact that a Black woman played an integral role in its development is comparatively underpublicized. During a month intended to celebrate both historical and current Black trailblazers, it is of the utmost importance that the American public properly recognize Dr. Kizzmekia Corbett, who – through both her illustrious career and her contributions to the vaccine – remains a fine example of Black excellence in science.

Portrait of Corbett

Per BlackPast, Corbett was born on January 26, 1986, in Hurdle Mills, North Carolina. Even at an early age, Corbett was considered by her mother (Rhonda Brooks) as a “sweet little, opinionated detective” due to her intellectual curiosity. While attending Hillsborough High School, she interned for numerous research labs and enrolled in ProjectSEED, a program dedicated to providing supplemental STEM courses for exemplary math and science students. During her summers off from UMBC (which she attended on a Meyerhoff scholarship), Corbett worked under the National Institute of Health alongside Dr. Barney Graham in studying the way that the respiratory syncytial virus develops in children. According to Graham, her ambition and desire for success were apparent from the start; upon his asking of what she wanted to accomplish in her life, Corbett informed him that “[she wanted his] job.” Soon after she earned her PhD and became a postdoctoral fellow of the NIH, Corbett started working on the creation of a vaccine to combat SARS and MERS, two coronavirus diseases. She and her team were responsible for identifying the spike protein of both viruses; as a result, she was asked to lead a team of scientists enlisted by Moderna to finish developing an effective mRNA-based vaccine (NOTE: Per the CDC, “mRNA vaccines contain material [from the SARS-CoV-2 virus] that gives our cells instructions for how to make a harmless protein that is unique to the virus. [Once] our cells make copies of the protein, they destroy the genetic material from the vaccine.” After recognizing that the protein is an invader, the body will create T-memory cells and B-memory cells, which are responsible for preventing re-infection). Luckily for the general public, her and her team’s efforts proved to be successful, as the Moderna vaccine has an impressively high efficacy rate. 

Corbett’s road to success wasn’t always easy; due to her race and gender, she was often deprived of a voice to share her research during times when it was desperately needed. Corbett was the only woman and Black person who was invited to now-former President Trump’s conference with leading figures of the NIH (including Dr. Anthony Fauci and Graham) regarding progress on the vaccine; according to NBC, no one at the meeting asked her a single question, despite her position as the head of the aforementioned scientific team leading the vaccine’s development. This treatment is not an anomaly: despite Graham’s stressing of the fact that Corbett is the leading expert on the project, many scientists around the globe defer to, direct questions to, and even double check her work with him instead. Even more egregious is the fact that Corbett is the subject of racist and sexist cyber abuse, as shown by this tweet telling her to “go back to McDonalds where [she belongs].”

Nevertheless, Corbett has made it clear (via an interview with Black Enterprise) that she never intends to change who she is and what motivates her in order to fit the expectations of the (increasingly diverse, but still largely white) STEM community. “I am Christian,” she says. “I’m Black. I am Southern, I’m an empath. I’m feisty, sassy, and fashionable. That’s kind of how I describe myself. I would say that my role as a scientist is really about my passion and purpose for the world and for giving back to the world.” By giving back to the world in such a formative way through her research, Corbett has proven that the growing desire for diversity in science is not just an option, but a necessity.

PCR? Rapid? Antibody? Are these tests really accurate? Here is your guide to Covid-19 testing

As we are entering what seems to be a second wave of the coronavirus outbreak, how should we approach getting tested and should we be relying on our results? 

According to the article written by John Ingold of the Colorado Sun, there are many tests that are used to test traces of SARS-CoV-2 but knowing when and what you are taking is crucial to stop the spread.  Covid-19 is a severe acute respiratory syndrome that has quickly caused a global pandemic. SARS-CoV-2 is a single stranded RNA-enveloped virus that contains spike proteins that allow viruses to penetrate host cells and cause infection. These spike proteins are divided up into two subunits, the S1 subunit and the S2 subunit. Once the S1 subunit binds to host cell receptors, two changes must occur for the S2 subunit to complete the fusion of the virus to the cell membrane. To test for coronavirus, the FDA has approved 170 different diagnostic tests and 47 blood tests for the virus. These tests are now being given out nationwide so they are more accessible to everyone but studies have questioned the accuracy of these tests. However, due to the numerous amounts of tests, it is crucial to know the differences and to learn which tests are right for your specific situations.

Blood Tests vs Diagnostic Tests

Blood tests, which are also called serological tests, test the blood for antibodies. Antibodies are indicators that your body has produced a immune response to the virus. The immune system protects the body against pathogens such as viruses and bacteria. In this case, the innate immunity is used to fight off Covid-19. Innate immunity is a defense that is active immediately upon infection. It is the first and second lines of defense and is a very rapid response. B cells within your body react to invading pathogens which causes the antibody to control the infection. These blood tests are usually used to test whether you have been previously infected by the virus but will occasionally detect whether you have the virus at that moment.

Diagnostic tests use other types of bodily fluids such as nasal mucus or saliva to test for an active infection. As you may have seen, they use long Q-tip swabs to swab the inside of your nose or mouth which they then send to a lab.

Sensitivity vs Specificity

When telling whether or not a test is accurate you must keep in mind the sensitivity and the specificity of the test.

Sensitivity tells whether or not the test is able to accurately detect the presence of an active virus. The less amount of sensitivity, the higher chance of receiving a false negative.

Specificity tells whether or not the test is able to accurately rule out the presence of an active virus. The less amount of specificity, the higher chance of receiving a false positive.

A guide to testing: 

Antibody Tests: As stated previously, antibody tests tend to be more sensitive than they are specific. The FDA found that most antibody tests have sensitivity values near 100% but specificity values near mid-90’s. This leads to an increase in false positives. The FDA also found that in some antibody tests, the positive predicting values are under 60% which means that it is very possible that there is a 50% percent chance that you actually have them and a 50% chance you don’t. Ultimately, these tests are sometimes quite unreliable.

PCR Tests: The PCR test, polymerase chain reaction, is a test that searches for the virus’ genetic material. The PCR test increases the genetic material so that it reaches detectable levels. These tests are administered by Q-tip swaps and take a few days to process them. The PCR is considered the most accurate test available and many say that if you have symptoms or have been exposed, this is the test for you.

Rapid Tests: Rapid tests have become increasingly common as they are faster and more consumer-friendly. However, scientists warn people that they are best used to determine if your cold is actually a cold or if it is Covid-19. If you are asymptomatic, they suggest a PCR test. Emily Travanty, interim director of the Colorado Department of Public Health and Environment’s state and public health lab, warns that the rapid test is significantly less sensitive which in case may lead to false negatives.

Antigen Tests: Antigen tests for the virus by looking for which specific proteins are on the surface of the virus. These tests are highly specific so are unlikely to deliver false positives and more likely to give false negatives. If you are being tested repeatedly, antigen tests are the best for you. However, if you are only getting tested occasionally, you should get a PCR test in order to confirm your results.

By knowing which type of test you should get in your specific situation, you are helping the cause of stopping the spread. As we enter what many people are starting the call the “second wave” it is crucial to get tested constantly in order to protect those we love. (Note that if you have been exposed it is recommended to isolate for a week at home before getting tested as the the virus needs time to accumulate. Testing too rapidly will increase your chance of getting a false negative.)

Monoclonal Antibodies: The Coronavirus Neutralizer

        An article published by ScienceNews discusses the possible usage of lab-made monoclonal antibodies to treat COVID-19 patients. The first study surrounding monoclonal antibodies suggests that monoclonal antibody drugs can help reduce the number of COVID-19 patients who need a ventilator. The second study explores how the monoclonal antibody drugs can help reduce the amount of COVID-19 viruses in the body, and it explores what the ideal dosage would be to induce the best results to fight against COVID-19.

        In general, antibodies attach to a specific antigen on a virus or infection to send signals to the cell to attack the invader. Monoclonal antibodies can be specifically made to target a specific virus and reduce its ability to replicate, namely, the coronavirus. One of these lab-made monoclonal antibodies is tocilizumab, which reduces inflammation caused by the coronavirus. The first trial of tocilizumab done by Genentech, a biotechnology company, was composed of 452 people who had severe COVID-19 symptoms. It was found that tocilizumab did not reduce the likelihood of death or decrease the intensity of symptoms. However, in phase three of the second trial, Genentech found that out of 389 patients hospitalized due to coronavirus infection that were given tocilizumab were 44% less likely to need a ventilator.

        Tocilizumab can also help combat cytokine storms- a very dangerous reaction to the coronavirus. When a pathogen- the coronavirus in this case- enters the cell, mast cells release histamine. Large phagocytic cells also release cytokines to trigger an innate cellular defense. During a cytokine storm, a large number of cytokines (a type of immune system protein) are secreted. This large amount creates an immune response in which human cells start to attack their own cells. Mukesh Kuma, an immunologist at Georgia State University in Atlanta found that the amount of cytokines produced as a result of SARS-CoV-2 infections is almost 50 times higher than Zika or West Nile virus infections.

        The article also discusses the use of LY-CoV555. LY-CoV555 is another type of monoclonal antibody. It specifically targets the coronavirus’ spike protein. The spike proteins on the coronavirus attach to the ACE2 receptor protein on human cells. This activates the A2 domain, and the virus can then fuse with the host cell membrane. By doing so, the spike protein acts as a key to get into the cell. The virus does not have to undergo receptor-mediated endocytosis, so the virus can enter the cell without a phospholipid membrane enclosing it. By attacking this spike protein, the LY-CoV55 destroys the virus’s ability to enter the cell. After discovering that LY-CoV555 was successful in reducing coronavirus symptoms, scientists conducted tests to find the ideal amount of LY-CoV555 dosage. They found that those who were given a “medium” amount of the dosage had the most success; 1.7 % of people with the medium dosage ended up being hospitalized, while about 9% of people who received a placebo were hospitalized. 

        Bamlanivimab is another type of monoclonal antibody specific for the spike protein of SARS-CoV-2. It also stops the coronavirus from attaching to the ACE2 receptor protein and prevents it from passing through the human cell membrane to its interior. On November 9th, 2020, the FDA recently allowed the emergency use of the Bamlanivimab antibody for those infected by the virus that is twelve years or older and is at high risk for the deadly side effects of the coronavirus.

        Rajesh Gandhi, an infectious disease physician at Harvard Medical School, and other scientists think that these trials are an important step, as they show that an monoclonal antibody is having an antiviral effect. While I have experienced any of the monoclonal antibody drugs, I think that they are a progressive move. If monoclonal antibodies can be distributed to various countries, I think that they could be a useful temporary solution for the coronavirus while the world awaits a vaccine in the coming winter months. 

        Do you think monoclonal antibodies could be helpful to COVID-19 patients? Would you prefer monoclonal antibody drugs to a COVID-19 vaccine? Comment down below!

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