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Immune Interference: Why Even ‘Up-to-Date’ Vaccines Might Have a Difficulty Keeping Up with Emerging Coronavirus Strains

Nurse Natalie O’Connor loads syringes with Moderna COVID-19 vaccine in February 2021. Joseph Prezioso / AFP via Getty Images Despite the success and optimism of the new COVID-19 vaccination campaigns being rolled out in Around the world, the emergence of new viral strains threatens to undermine their effectiveness. Indeed, South Africa has been forced to rethink its strategy as the initial vaccine it chose did not provide protection to an emerging but now dominant viral variant. There is still much hope that the mRNA-based vaccines licensed in the US, with their spectacular efficacy, will continue to provide protection despite the alteration of the selection of new strains. The jury is still out on viral vector vaccines, such as Johnson & Johnson’s new vaccine, but early data showing reduced effectiveness against the South African variant has raised alarms. RNA viruses, like coronaviruses, are known for their ability to mutate. With continued and widespread infection, the chance that the virus will mutate and bypass ongoing vaccination efforts remains high. Many members of the scientific community have been comfortable knowing that mRNA-based vaccines can be quickly modified and re-implemented. If our current vaccines fail, we revaccinate people with outdated immunity against the new strains and play global whack-a-mole as the virus evolves. But it may not be that easy. As an immunologist studying how antibody responses choose their targets, I am concerned that these “vaccine updates” may be less effective in patients who have already received their original injections. Immune memory, the very thing that offers continuous protection against a virus long after vaccination, can sometimes negatively interfere with the development of mildly updated immune responses. The scientific community must anticipate this emerging problem and investigate vaccine approaches that are known to reduce the potential for viral escape. Former FDA Commissioner Dr. Scott Gottlieb discusses variants of the coronavirus and how to adapt to them. Vaccines are designed to build immune memory. In simpler terms, vaccines are a way to give your immune system a sneak peek at a pathogen. There are different ways to do this. One way is to inject inactivated versions of a virus, as has been done with polio. Another is to use non-infectious viral components, such as the proteins used in flu vaccines. And more recently, scientists have found ways to deliver mRNA “instructions” that tell your body how to make those non-infectious viral components, as has been done with the Moderna and Pfizer COVID-19 vaccines. All of these vaccines train your immune system to identify and respond against critical components of a potential invader. An important part of that response is getting your body to make antibodies that hopefully prevent future infections, breaking the cycle of person-to-person transmission. However, your immune system takes time to generate those protective responses. Your immune system is immensely powerful, capable of destroying dangerous pathogens as well as your own tissue. The risk of accidentally producing antibodies that attack your own body is very real and potentially catastrophic. To prevent this, your immune system rigorously tests antibody-producing immune cells, called B cells, to make sure they respond with high specificity to the pathogen and not to your own tissue. This process can take weeks. Rushing it carries risks and can be a major component of severe COVID-19 manifestations. Vaccination gives your body the time to carry out this process safely, generating antibodies against the pathogen that pose no risk to your own cells. The antibodies you make in that time will last for months, and your immune system also remembers how to make them. Establishing immunological memory is a critical component of vaccines. The ability to remember what your immune system has responded to in the past gives you a significant advantage when encountering the same pathogen in the future. But what happens when the virus evolves and that memory becomes “out of date”? MRNA vaccines work differently from older vaccines. The spectrum of ‘original antigenic sin’ During a response to a pathogen, such as a virus, your immune system produces large amounts of a limited set of antibodies. Think of a virus as a car trying to run you over. It can produce a type of antibody against the hood, one against the bumper, and one against the hubcaps that prevents the wheels from spinning. It has produced three types of antibodies that are specific to the car, but only the antibodies from the hubcap will slow down the car. Your immune system will remember how to produce all three and does not distinguish between them. Now the car-virus mutates. Change the changes in the shape of the hubcaps, change the material or remove them entirely. Your immune system will remember the car, but not the hubcaps. The system doesn’t know that targeting the hubcap was the only important part, so it will increase its attack on the hood and bumper, minimizing the importance of all other answers. You can “tweak” your hubcap response, or maybe even develop a new one from scratch, but that process will be slow and certainly of lower priority. By ignoring the new hubcap response, the memory of the original car’s immune system is not only outdated, it actively interferes with the response needed to target the new car’s wheels. This is what immunologists call “original antigenic sin” – ineffective immune memory that hinders desired responses to new strains of pathogens. This phenomenon is well documented in influenza, where seasonal variants and repeat vaccines dominate the landscape. However, this type of interference is extraordinarily difficult to quantify, making it difficult to study routinely. Scientists and public health officials cannot ignore this threat in COVID-19 and must get ahead of the virus. Fortunately, there is a way to go. [Get the best of The Conversation, every weekend. Sign up for our weekly newsletter.] Multi-Strain Vaccines Offer Hope To combat this problem, major efforts are underway to prioritize the search for either a single-shot flu vaccine or a universal vaccine. The goal is to create a vaccine capable of neutralizing many different viral strains at the same time. To this end, researchers have begun to advance the development and use of complex multi-strain vaccines, taking advantage of emerging research showing that if your immune system is presented with multiple versions of the same pathogen, it will tend to choose targets that are shared. among them. Featured with a Model-T, a Ford F150, and an electric Mustang all at once, your immune system will often choose to ignore the differences between targets. Instead of concentrating on the hood, or even the easily modifiable hubcaps, your immune system could recognize the shape and rubber of the tires. This altered response would not only interfere with the function of the three vehicles, but would be directed at a region of the vehicle that is generalized. It has not created a vaccine against Mustangs, it has created a vaccine against road vehicles that use tires. Newly acquired knowledge about influenza vaccination should be applied immediately to SARS-CoV-2. I am hopeful that the current class of mRNA vaccines will continue to provide protection against emerging strains, but this pandemic has taught us that hope is not enough. Over the past year, governments around the world have stepped up to provide resources for basic research on immune responses to COVID-19 and ongoing vaccination efforts. They had the foresight and courage to fund a new mRNA-based vaccination technology that has ushered in a new era in vaccination. Let’s build on that momentum and prioritize researching truly innovative approaches to vaccination that can benefit billions of people around the world. This article is republished on The Conversation, a nonprofit news site dedicated to sharing ideas from academic experts. It was written by: Matthew Woodruff, Emory University. Read more: Johnson & Johnson’s COVID-19 Vaccine Backlash is Real and Risky – Here’s How to Make Your Launch a Success Two Gaps to Fill for the 2021-2022 Winter Wave of COVID-19 Cases Matthew Woodruff’s research is supported by the National Institutes of Health. He is also a co-founder of the Jefferson electorate.

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