Virus World

Life-threatening responses seen in at least eight people could be linked to polyethylene glycol, known to trigger reactions to some drugs. Severe allergy-like reactions in at least eight people who received the COVID-19 vaccine produced by Pfizer and BioNTech over the past 2 weeks may be due to a compound in the packaging of the messenger RNA (mRNA) that forms the vaccine’s main ingredient, scientists say. A similar mRNA vaccine developed by Moderna, which was authorized for emergency use in the United States on Friday, also contains the compound, polyethylene glycol (PEG). PEG has never been used before in an approved vaccine, but it is found in many drugs that have occasionally triggered anaphylaxis—a potentially life-threatening reaction that can cause rashes, a plummeting blood pressure, shortness of breath, and a fast heartbeat. Some allergists and immunologists believe a small number of people previously exposed to PEG may have high levels of antibodies against PEG, putting them at risk of an anaphylactic reaction to the vaccine.  Others are skeptical of the link. Still, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) was concerned enough to convene several meetings last week to discuss the allergic reactions with representatives of Pfizer and Moderna, independent scientists and physicians, and the Food and Drug Administration (FDA). NIAID is also setting up a study in collaboration with FDA to analyze the response to the vaccine in people who have high levels of anti-PEG antibodies or have experienced severe allergic responses to drugs or vaccines before. “Until we know there is truly a PEG story, we need to be very careful in talking about that as a done deal,” says Alkis Togias, branch chief of allergy, asthma and airway biology at NIAID. Pfizer, too, says it is “actively seeking follow-up.” A statement emailed to Science noted it already recommends that “appropriate medical treatment and supervision should always be readily available” in case a vaccinee develops anaphylaxis.

Anaphylactic reactions can occur with any vaccine, but are usually extremely rare—about one per 1 million doses. As of 19 December, the United States had seen six cases of anaphylaxis among 272,001 people who received the COVID-19 vaccine, according to a recent presentation by Thomas Clark of the U.S. Centers for Disease Control and Prevention (CDC); the United Kingdom has recorded two. Because the Pfizer and Moderna mRNA vaccines use a new platform, the reactions call for careful scrutiny, says Elizabeth Phillips, a drug hypersensitivity researcher at Vanderbilt University Medical Center who attended an NIAID meeting on 16 December. “This is new.”  News reports about the allergic reactions have already created anxiety. “Patients with severe allergies in the US are getting nervous about the possibility that they may not be able to get vaccinated, at least with those two vaccines,” Togias wrote in an invitation to meeting participants. “Allergies in general are so common in the population that this could create a resistance against the vaccines in the population,” adds Janos Szebeni, an immunologist at Semmelweis University in Budapest, Hungary, who has long studied hypersensitivity reactions to PEG and who also attended the 16 December gathering. Scientists who believe PEG may be the culprit stress that vaccination should continue. “We need to get vaccinated,” Phillips says. “We need to try and curtail this pandemic.” But more data are urgently needed, she adds: “These next couple of weeks in the U.S. are going to be extremely important for defining what to do next.”

Toothpaste and shampoo

Pfizer’s and Moderna’s clinical trials of the vaccines, which involved tens of thousands of people, did not find serious adverse events caused by the vaccine. But both studies excluded people with a history of allergies to components of the COVID-19 vaccines; Pfizer also excluded those who previously had a severe adverse reaction from any vaccine. People with previous allergic reactions to food or drugs were not excluded, but may have been underrepresented. The two vaccines both contain mRNA wrapped in lipid nanoparticles (LNPs) that help carry it to human cells but also act as an adjuvant, a vaccine ingredient that bolsters the immune response. The LNPs are “PEGylated”—chemically attached to PEG molecules that cover the outside of the particles and increase their stability and life span. PEGs are also used in everyday products such as toothpaste and shampoo as thickeners, solvents, softeners, and moisture carriers, and they’ve been used as a laxative for decades. An increasing number of biopharmaceuticals include PEGylated compounds as well. PEGs were long thought to be biologically inert, but a growing body of evidence suggests they are not. As much as 72% of people have at least some antibodies against PEGs, according to a 2016 study led by Samuel Lai, a pharmaco-engineer at the University of North Carolina, Chapel Hill, presumably as a result of exposure to cosmetics and pharmaceuticals. About 7% have a level that may be high enough to predispose them to anaphylactic reactions, he found. Other studies have also found antibodies against PEG, but at lower levels. “Some companies have dropped PEGylated products from their pipeline as a result,” Lai says. But he notes that the safety record of many PEGylated drugs has persuaded others that “concerns about anti-PEG antibodies are overstated. Szebeni says the mechanism behind PEG-conjugated anaphylaxis is relatively unknown because it does not involve immunoglobulin E (IgE), the antibody type that causes classical allergic reactions. (That’s why he prefers to call them “anaphylactoid” reactions.) Instead, PEG triggers two other classes of antibodies, immunoglobulin M (IgM) and immunoglobulin G (IgG), involved in a branch of the body’s innate immunity called the complement system, which Szebeni has spent decades studying in a pig model he developed...

The fight against drug-resistant pathogens remains an intense one. While the Centers for Disease Control's (CDC) 2019 "biggest threats" report reveals an overall decrease in drug-resistant microbe-related deaths as compared to its previous report (2013) the agency also cautions that new forms of drug-resistant pathogens are still emerging. Meanwhile, the options for treating infections by these germs are diminishing, confirming doctors' and scientists' worries about the end of the age of antibiotics.

"We knew it was going to be a problem early on," said UC Santa Barbara chemistry and biochemistry professor Irene Chen. "Basically as soon as penicillin was discovered, a few years later it was reported that there was a resistant organism." Thanks to factors such as horizontal gene transfer and rapid reproduction, organisms such as Gram-negative bacteria are able to evolve faster than we can produce antibiotics to control them. So Chen and her research group are seeking alternatives to antibiotics, in a growing effort to head off the tide of incurable bacterial infections. In their work, the group has turned to bacteriophages, a naturally occurring group of viruses that colonize on bacteria. "That's their natural function, really, to grow on and kill bacteria," said Chen, author of a paper that appears in the Proceedings of the National Academy of Sciences. By taking advantage of the bacteriophages' ability to home in on specific bacteria without damaging the rest of the microbiome, the researchers were able to use a combination of gold nanorods and near-infrared light to destroy even multidrug-resistant bacteria without antibiotics. Phage therapy isn't new, Chen said. In fact, it have been used in the former Soviet Union and Europe for about a century, though they are seen largely as last-resort alternatives to antibiotics. Among the unresolved issues of phage therapy is the incomplete characterization of the phages' biology—a biology that could allow for unintended consequences due to the phages' own rapid evolution and reproduction, as well as potential toxins the viruses may carry. Another issue is the all-or-nothing aspect of phage therapy, she added. "It's difficult to analyze the effect of a phage treatment," she said. "You might see it completely work or you might see it completely fail, but you don't have the kind of dose response you want."

To surmount these challenges, the Chen lab developed a method of controlled phage therapy. "What we did was to conjugate the phages to gold nanorods," she explained. These "phanorods" were applied to bacteria on in-vitro cultures of mammalian cells and then exposed to near-infrared light. "When these nanorods are photo-excited, they translate the energy from light to heat," Chen said, "and that creates very high local temperatures." The heat is enough to kill the bacteria, and it also kills the phages, preventing any unwanted further evolutions. The result is a guided missile of targeted phage therapy that also allows for dosage control. The lab found success in destroying E. coli, P. aeruginosa and V. cholerae—human pathogens that cause acute symptoms if left unchecked. They also were able to successfully destroy X. campestris, a bacteria that causes rot in plants....

Published in PNAS (January 13, 2020):

https://doi.org/10.1073/pnas.1913234117

Researchers at Georgia State University.develop universal flu vaccine that protects against six influenza viruses in mice. The researchers developed and showed that a novel nanoparticle vaccine that combines two major influenza proteins is effective in providing broad, long-lasting protection against the influenza virus in mice, showing promise as a universal flu vaccine. Findings from the new study—performed in mice and published recently in Advanced Healthcare Materials through an article titled “Double‐Layered M2e‐NA Protein Nanoparticle Immunization Induces Broad Cross‐Protection against Different Influenza Viruses in Mice”—suggest this unique vaccine combination has potential as a universal influenza vaccine or component of such vaccines.

The double-layered nanoparticle vaccine contains the influenza virus proteins matrix protein 2 ectodomain (M2e) and neuraminidase (NA). Mice were immunized with the nanoparticle vaccine before being exposed to the influenza virus, and they were protected against six different strains of the virus. “This nanoparticle antigen combination conferred mice with strong cross-protection,” explained lead study investigator Ye Wang, a doctoral candidate at the Institute for Biomedical Sciences. “It can protect mice from different strains of influenza virus. Each season, we have different flu strains that affect us. By using this approach, we hope this nanoparticle vaccine can protect humans from different strains of the influenza virus.”

Influenza is a leading cause of death by infection. Seasonal flu vaccines are insufficient to prevent influenza outbreaks and developing a universal influenza vaccine is the ideal strategy for eliminating public health threats of influenza epidemics and pandemics. A universal influenza vaccine would eliminate the need for vaccinations each season and offers universal protection against all influenza strains. The influenza virus protein M2e is found in all influenza virus strains, with each strain having a very similar version, and the protein has mutated very slowly over time. The protein NA is found on the surface of the influenza virus and has also mutated much slower than other influenza proteins. This double-layered nanoparticle vaccine uses M2e as its core, and NA is coated on the surface. In the current study, mice were exposed to one of six influenza virus strains after receiving the nanoparticle vaccine by intramuscular injection. The vaccine proved to have long-lasting immune protection, which was unchanged against viral challenges up to four months after immunizations. 

Published in Advanced Healthcare Materials (Dec. 15, 2019):

https://doi.org/10.1002/adhm.201901176