Study shows promise for a universal influenza vaccine

New research led by Oregon Health & Science University reveals a promising approach to developing a universal influenza vaccine -- a so-called "one and done" vaccine that confers lifetime immunity against an evolving virus.

The study, published today in the journal Nature Communications, tested an OHSU-developed vaccine platform against the virus considered most likely to trigger the next pandemic.

Researchers reported the vaccine generated a robust immune response in nonhuman primates that were exposed to the avian H5N1 influenza virus. But the vaccine wasn't based on the contemporary H5N1 virus; instead, the primates were inoculated against the influenza virus of 1918 that killed millions of people worldwide.

"It's exciting because in most cases, this kind of basic science research advances the science very gradually; in 20 years, it might become something," said senior author Jonah Sacha, Ph.D., professor and chief of the Division of Pathobiology at OHSU's Oregon National Primate Research Center. "This could actually become a vaccine in five years or less."

Researchers reported that six of 11 nonhuman primates inoculated against the virus that circulated a century ago -- the 1918 flu -- survived exposure to one of the deadliest viruses in the world today, H5N1. In contrast, a control group of six unvaccinated primates exposed to the H5N1 virus succumbed to the disease.

Sacha said he believes the platform "absolutely" could be useful against other mutating viruses, including SARS-CoV-2.

"It's a very viable approach," he said. "For viruses of pandemic potential, it's critical to have something like this. We set out to test influenza, but we don't know what's going to come next."

A senior co-author from the University of Pittsburgh concurred.

"Should a deadly virus such as H5N1 infect a human and ignite a pandemic, we need to quickly validate and deploy a new vaccine," said co-corresponding author Douglas Reed, Ph.D., associate professor of immunology at the University of Pittsburgh Center for Vaccine Research.

Finding a stationary target

This approach harnesses a vaccine platform previously developed by scientists at OHSU to fight HIV and tuberculosis, and in fact is already being used in a clinical trial against HIV.

The method involves inserting small pieces of target pathogens into the common herpes virus cytomegalovirus, or CMV, which infects most people in their lifetimes and typically produces mild or no symptoms. The virus acts as a vector specifically designed to induce an immune response from the body's own T cells.

This approach differs from common vaccines -- including the existing flu vaccines -- which are designed to induce an antibody response that targets the most recent evolution of the virus, distinguished by the arrangement of proteins covering the exterior surface.

"The problem with influenza is that it's not just one virus," Sacha said. "Like the SARS-CoV-2 virus, it's always evolving the next variant and we're always left to chase where the virus was, not where it's going to be."

The spike proteins on the virus exterior surface evolve to elude antibodies. In the case of flu, vaccines are updated regularly using a best estimate of the next evolution of the virus. Sometimes it's accurate, sometimes less so.

In contrast, a specific type of T cell in the lungs, known as effector memory T cell, targets the internal structural proteins of the virus, rather than its continually mutating outer envelope. This internal structure doesn't change much over time -- presenting a stationary target for T cells to search out and destroy any cells infected by an old or newly evolved influenza virus.

Success with a century-old template

To test their T cell theory, researchers designed a CMV-based vaccine using the 1918 influenza virus as a template. Working within a highly secure biosafety level 3 laboratory at the University of Pittsburgh, they exposed the vaccinated nonhuman primates to small particle aerosols containing the avian H5N1 influenza virus -- an especially severe virus that is currently circulating among dairy cows in the United States.

Remarkably, six of the 11 vaccinated primates survived the exposure, despite the century-long period of virus evolution.

"It worked because the interior protein of the virus was so well preserved," Sacha said. "So much so, that even after almost 100 years of evolution, the virus can't change those critically important parts of itself."

The study raises the potential for developing a protective vaccine against H5N1 in people.

"Inhalation of aerosolized H5N1 influenza virus causes a cascade of events that can trigger respiratory failure," said co-senior author Simon Barratt-Boyes, Ph.D., professor of infectious diseases, microbiology and immunology at Pitt. "The immunity induced by the vaccine was sufficient to limit virus infection and lung damage, protecting the monkeys from this very serious infection."

By synthesizing more up-to-date virus templates, the new study suggests CMV vaccines may be able to generate an effective, long-lasting immune response against a wide suite of new variants.

"I think it means within five to 10 years, a one-and-done shot for influenza is realistic," Sacha said.

The same CMV platform developed by OHSU researchers has advanced to a clinical trial to protect against HIV, and a recent publication by those scientists suggests it may even be useful targeting specific cancer cells. The HIV clinical trial is being led by Vir Biotechnology, which licensed the vaccine platform from OHSU.

Sacha sees the development as the latest in the rapid advance of medical research to treat or prevent disease.

"It's a massive sea change within our lifetimes," Sacha said. "There is no question we are on the cusp of the next generation of how we address infectious disease."

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Macaque trials offer hope in pneumonia vaccine development

The global impact of the coronavirus pandemic has ignited a renewed focus on emerging and re-emerging infectious diseases. Researchers at Osaka Metropolitan University are making great strides in combating pneumococcal pneumonia, one of the leading causes of respiratory deaths worldwide.

Despite the existence of vaccines against pneumococcal infections such as otitis media, sinusitis, and meningitis, the prevalence of pneumococcal pneumonia remains high.

Currently, around 100 new serotypes of Streptococcus pneumoniae have been identified, and the increase in pneumococcal infections caused by serotypes not covered by the vaccine has become a concern.

This situation underscores the need for a more versatile vaccine.

Building on their previous success in mucosal responses in 2019, in which they developed a mucosal vaccine that caninduce antigen-specific mucosal immune responses, mainly immunoglobulin A (IgA), on the target mucosal surface, a research team led by Professor Satoshi Uematsu and Associate Professor Kosuke Fujimoto from the Department of Immunology and Genomics at the Graduate School of Medicine, Osaka Metropolitan University, has this time set out to bridge the gap in pneumococcal pneumonia vaccination efficacy.

To successfully develop a novel pneumococcal vaccine, the research team combined its proprietary mucosal vaccine technology with pneumococcal surface proteins that can cover a wide range of serotypes.

Experiments conducted on mice and macaques have demonstrated the vaccine's efficacy in suppressing pneumococcal pneumonia in the target animal groups.

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Engineers design more powerful RNA vaccines

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven't yet been used in RNA vaccines. In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers' tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

"With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body," says Daniel Anderson, a professor in MIT's Department of Chemical Engineering, a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. "Intranasal vaccines may also be easier to administer to many people, since they don't require an injection."

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children's Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus's spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d's role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.

"With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems," Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are "ionizable" lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

"We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response," Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

"For the first time, we've demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles," Li says. "This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways."

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs.

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

Read more at Science Daily

ChatGPT is debunking myths on social media around vaccine safety, say experts

ChatGPT could help to increase vaccine uptake by debunking myths around jab safety, say the authors of a study published in the peer-reviewed journal Human Vaccines and Immunotherapeutics.

The researchers asked the artificial intelligence (AI) chatbot the top 50 most frequently-asked Covid-19 vaccine questions. They included queries based on myths and fake stories such as the vaccine causing Long Covid.

Results show that ChatGPT scored nine out of 10 on average for accuracy. The rest of the time it was correct but left some gaps in the information provided, according to the study.

Based on these findings, experts who led the study from the GenPoB research group based at the Instituto de Investigación Sanitaria (IDIS) -- Hospital Clinico Universitario of Santiago de Compostela, say the AI tool is a "reliable source of non-technical information to the public," especially for people without specialist scientific knowledge.

However, the findings do highlight some concerns about the technology such as ChatGPT changing its answers in certain situations.

"Overall, ChatGPT constructs a narrative in line with the available scientific evidence, debunking myths circulating on social media," says lead author Antonio Salas, who as well as leading the GenPoB research group, is also a Professor at the Faculty of Medicine at the University of Santiago de Compostela, in Spain.

"Thereby it potentially facilitates an increase in vaccine uptake. ChatGPT can detect counterfeit questions related to vaccines and vaccination. The language this AI uses is not too technical and therefore easily understandable to the public but without losing scientific rigor.

"We acknowledge that the present-day version of ChatGPT cannot substitute an expert or scientific evidence. But the results suggest it could be a reliable source of information to the public."

In 2019, the World Health Organisation (WHO) listed vaccine hesitancy among the top 10 threats to global health.

During the pandemic, misinformation spread via social media contributed to public mistrust of Covid-19 vaccination.

The authors of this study include those from the Hospital Clinico Universitario de Santiago which the WHO designated as a vaccine safety collaborating center in 2018.

Researchers at the center have been exploring myths around vaccine safety and medical situations that are falsely believed to be a reason not to get vaccinated. These misplaced concerns contribute to vaccine hesitancy.

The study authors set out to test ChatGPT's ability to get the facts right and share accurate information around Covid vaccine safety in line with current scientific evidence.

ChatGPT enables people to have human-like conversations and interactions with a virtual assistant. The technology is very user-friendly which makes it accessible to a wide population.

However, many governments are concerned about the potential for ChatGPT to be used fraudulently in educational settings such as universities.

The study was designed to challenge the chatbot by asking it the questions most frequently received by the WHO collaborating center in Santiago.

The queries covered three themes. The first was misconceptions around safety such as the vaccine causing Long Covid. Next was false contraindications -- medical situations where the jab is safe to use such as in breastfeeding women.

The questions also related to true contraindications -- a health condition where the vaccine should not be used -- and cases where doctors must take precautions e.g. a patient with heart muscle inflammation.

Next, experts analyzed the responses then rated them for veracity and precision against current scientific evidence, and recommendations from WHO and other international agencies.

The authors say this was important because algorithms created by social media and internet search engines are often based on an individual's usual preferences. This may lead to 'biased or wrong answers', they add.

Results showed that most of the questions were answered correctly with an average score of nine out of 10 which is defined as 'excellent' or 'good'. The responses to the three question themes were on average 85.5% accurate or 14.5% accurate but with gaps in the information provided by ChatGPT.

ChatGPT provided correct answers to queries that arose from genuine vaccine myths, and to those considered in clinical recommendation guidelines to be false or true contraindications.

However, the research team does highlight ChatGPT's downsides in providing vaccine information.

Professor Salas, who specializes in human genetics, concludes: "Chat GPT provides different answers if the question is repeated 'with a few seconds of delay'.

"Another concern we have seen is that this AI tool, in its present version, could also be trained to provide answers not in line with scientific evidence.

"One can 'torture' the system in such a way that it will provide the desired answer. This is also true for other contexts different to vaccines. For instance, it might be possible to make the chatbot align with absurd narratives like the flat-earth theory, deny climate change, or object to the theory of evolution, just to give a few examples.

Read more at Science Daily

Transforming the way cancer vaccines are designed and made

A new way to significantly increase the potency of almost any vaccine has been developed by researchers from the International Institute for Nanotechnology (IIN) at Northwestern University. The scientists used chemistry and nanotechnology to change the structural location of adjuvants and antigens on and within a nanoscale vaccine, greatly increasing vaccine performance. The antigen targets the immune system, and the adjuvant is a stimulator that increases the effectiveness of the antigen.

The scientists used chemistry and nanotechnology to change the structural location of adjuvants and antigens on and within a nanoscale vaccine, greatly increasing vaccine performance. The antigen targets the immune system, and the adjuvant is a stimulator that increases the effectiveness of the antigen.

The study will be published Jan. 30 in Nature Biomedical Engineering.

"The work shows that vaccine structure and not just the components is a critical factor in determining vaccine efficacy," said lead investigator Chad A. Mirkin, director of the IIN. "Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognizes and processes it.

Mirkin also is the George B. Rathmann Professor of Chemistry at the Weinberg College of Arts and Sciences and a professor of medicine at Northwestern University Feinberg School of Medicine.

This new heightened emphasis on structure has the potential to improve the effectiveness of conventional cancer vaccines, which historically have not worked well, Mirkin said.

Mirkin's team has studied the effect of vaccine structure in the context of seven different types of cancer to date, including triple-negative breast cancer, papillomavirus-induced cervical cancer, melanoma, colon cancer and prostate cancer to determine the most effective architecture to treat each disease.

Conventional vaccines take a blender approach

With most conventional vaccines, the antigen and the adjuvant are blended and injected into a patient. There is no control over the vaccine structure, and, consequently, limited control over the trafficking and processing of the vaccine components. Thus, there is no control over how well the vaccine works.

"A challenge with conventional vaccines is that out of that blended mish mosh, an immune cell might pick up 50 antigens and one adjuvant or one antigen and 50 adjuvants," said study author and former Northwestern postdoctoral associate Michelle Teplensky, who is now an assistant professor at Boston University. "But there must be an optimum ratio of each that would maximize the vaccine's effectiveness."

Enter SNAs (spherical nucleic acids), which are the structural platform -- invented and developed by Mirkin -- used in this new class of modular vaccines. SNAs allow scientists to pinpoint exactly how many antigens and adjuvants are being delivered to cells. SNAs also enable scientists to tailor how these vaccine components are presented, and the rate at which they are processed. Such structural considerations, which greatly impact vaccine effectiveness, are largely ignored in conventional approaches.

Vaccines developed through 'rational vaccinology' offer precise dosing for maximum effectiveness

This approach to systematically control antigen and adjuvant locations within modular vaccine architectures was created by Mirkin, who coined the term rational vaccinology to describe it. It is based on the concept that the structural presentation of vaccine components is as important as the components themselves in driving efficacy.

"Vaccines developed through rational vaccinology deliver the precise dose of antigen and adjuvant to every immune cell, so they are all equally primed to attack cancer cells," said Mirkin, who also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "If your immune cells are soldiers, a traditional vaccine leaves some unarmed; our vaccine arms them all with a powerful weapon with which to kill cancer. Which immune cell 'soldiers' do you want to attack your cancer cells?" Mirkin asked rhetorically.

Building an (even) better vaccine

The team developed a cancer vaccine that doubled the number of cancer antigen-specific T cells and increased the activation of these cells by 30% by reconfiguring the architecture of the vaccine to contain multiple targets to help the immune system find tumor cells.

The team investigated differences in how well two antigens were recognized by the immune system depending on their placement -- on the core or perimeter -- of the SNA structure. For an SNA with optimum placement, they could increase the immune response and how quickly the nanovaccine triggered cytokine (an immune cell protein) production to boost T cells attacking the cancer cells. The scientists also studied how the different placements affected the immune system's ability to remember the invader, and whether the memory was long-term.

"Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognizes and processes it," Mirkin said.

The most powerful structure throws two punches to outsmart the wily, mutating tumor

The study data show that attaching two different antigens to an SNA comprising a shell of adjuvant was the most potent approach for a cancer vaccine structure. It led to a 30% increase in antigen-specific T-cell activation and doubled the number of proliferating T cells compared to a structure in which the same two antigens were attached to two separate SNAs.

These engineered SNA nanostructures stalled tumor growth in multiple animal models.

"It is remarkable," Mirkin said. "When altering the placement of antigens in two vaccines that are nearly identical from a compositional standpoint, the treatment benefit against tumors is dramatically changed. One vaccine is potent and useful, while the other is much less effective."

Many current cancer vaccines are designed to primarily activate cytotoxic T cells, only one defense against a cancer cell. Because tumor cells are always mutating, they can easily escape this immune cell surveillance, quickly rendering the vaccine ineffective. The odds are higher that the T cell will recognize a mutating cancer cell if it has more ways -- multiple antigens -- to recognize it.

"You need more than one type of T cell activated, so you can more easily attack a tumor cell," Teplensky said. "The more types of cells the immune system has to go after tumors, the better. Vaccines consisting of multiple antigens targeting multiple immune cell types are necessary to induce enhanced and long-lasting tumor remission."

Another advantage of the rational vaccinology approach, especially when used with a nanostructure like an SNA, is that it's easy to alter the structure of a vaccine to go after a different type of disease. Mirkin said they simply switch out a peptide, a snippet of a cancer protein with a chemical handle that "clips" onto the structure, not unlike adding a new charm to a bracelet.

Path to most effective vaccine for any cancer type

"The collective importance of this work is that it lays the foundation for developing the most effective forms of vaccine for almost any type of cancer," Teplensky said. "It is about redefining how we develop vaccines across the board, including ones for infectious diseases."

In a previously published paper, Mirkin, Teplensky and colleagues demonstrated the importance of vaccine structure for COVID-19 by creating vaccines that exhibited protective immunity in 100% of animals against a lethal viral infection.

"Small changes in antigen placement on a vaccine significantly elevate cell-to-cell communication, cross-talk and cell synergy," Mirkin said. "The developments made in this work provide a path forward to rethinking the design of vaccines for cancer and other diseases as a whole."

Read more at Science Daily

Scientists reveal encouraging findings in first-in-human clinical trial evaluating HIV vaccine approach

While scientists have struggled in the past to create an effective vaccine against HIV, a novel vaccine design strategy being pursued by researchers at Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) shows new promise, according to data from a first-in-human clinical trial.

In a paper published in Science on December 2, 2022, the scientists reveal critical new insights into their novel vaccine strategy, which involves a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants.

"The data we are publishing in Science demonstrates for the first time that one can design a vaccine that elicits made-to-order antibodies in humans. We specified in advance certain molecular properties of the antibodies that we wanted to elicit, and the results of this trial show that our vaccine antigen consistently induced precisely those types of antibodies," says co-senior author William Schief, PhD, a professor and immunologist at Scripps Research and executive director of vaccine design at IAVI's Neutralizing Antibody Center, whose laboratory developed the vaccine antigen. "We believe this vaccine design strategy will be essential to make an HIV vaccine and may help the field create vaccines for other difficult pathogens."

The Phase 1 trial, known as IAVI G001, tested the first stage in a multi-stage HIV vaccine regimen the researchers are developing. The trial results show that the vaccine had a favorable safety profile and induced the targeted response in 97% of people who were vaccinated. Importantly, the Science study also provides a detailed immunological analysis of the vaccine responses.

"HIV represents an area of dire unmet need across the world, which is what makes the findings from our Phase 1 clinical trial so encouraging," says Mark Feinberg, MD, PhD, president and CEO of IAVI. "Through the close-knit collaboration of many different scientists, disciplines and institutions, we are that much closer to designing an effective vaccine that could help end the HIV pandemic."

Priming the Immune System

Broadly neutralizing antibodies (bnAbs) are a rare type of antibody that can fight and protect against many different variants of a virus -- including HIV. This is why scientists have tried to develop an HIV vaccine that induces bnAbs, but thus far without success.

The researchers in the study are using a strategy known as 'germline targeting' to eventually produce bnAbs that can protect against HIV. The first step of germline targeting involves stimulating the rare immune cells -- known as bnAb-precursor B cells -- that can eventually evolve into the cells that produce the bnAbs needed to block the virus. To accomplish this first step, the researchers designed a customized molecule -- known as an immunogen -- that would "prime" the immune system and elicit responses from these rare bnAb-precursor cells.

The overarching goal of the IAVI G001 trial was to determine if the vaccine had an acceptable safety profile and could induce responses from these bnAb-precursor B cells.

"Through extensive safety and tolerability monitoring during the trial, we showed the vaccine had a favorable safety profile, while still inducing the necessary target cells," says study author Dagna Laufer, MD, vice president and head of clinical development at IAVI. "This represents a large step forward in developing an HIV vaccine that is both safe and effective."

To determine if the targeted bnAb-precursor B cells were induced, the researchers carried out a sophisticated analytical process.

"The workflow of multidimensional immunological analyses has taken clinical trial evaluation to the next level," says co-senior author Adrian B. McDermott, PhD, former chief of the Vaccine Immunology Program at the NIAID VRC. "In evaluating these important immunological factors, we helped show why the vaccine antigen was able to induce the targeted response in 97% of vaccine recipients."

IAVI G001 was sponsored by IAVI and took place at two sites: George Washington University (GWU) in Washington, D.C., and Fred Hutch in Seattle, enrolling 48 healthy adult volunteers. Participants received either a placebo or two doses of the vaccine antigen, eOD-GT8 60mer, along with an adjuvant developed by the pharmaceutical company GSK. Julie McElrath, MD, PhD, co-senior author, senior vice president and director of Fred Hutch's Vaccine and Infectious Disease Division, and David Diemert, MD, professor of medicine at GWU School of Medicine and Health Sciences, were lead investigators at the trial sites.

A Deeper Immunological Dive

The study also carefully examined the properties of the antibodies and B cells induced by the vaccine antigen, in what Schief likens to "looking under the car hood" to understand how the immune system operated in response to the vaccine. One analysis showed that the vaccine antigen first stimulated an average of 30 to 65 different bnAb precursors per person vaccinated, and then caused those cells to multiply. This helped explain why the vaccine induced the desired response in almost all participants.

Other analyses delved into the specific mutations the bnAb-precursor B cells acquired over time and how tightly they bound to the vaccine antigen. These investigations showed that that after each dose of the vaccine, the bnAb-precursor B cells gained affinity and continued along favorable maturation pathways.

One concern for this type of vaccine approach is the notion of "competitors" -- in other words, the B cells induced by the vaccine antigen that are not bnAb precursors. The researchers extensively studied the "competitor" responses, and the results were very encouraging. Although the majority of the B cells triggered by vaccination were, in fact, "competitors," these undesired B cells could not match the binding strength of the desired bnAb precursors and did not seem to impede maturation of the bnAb-precursor responses.

"These findings were very encouraging, as they indicated that immunogen design principles we used could be applied to many different epitopes, whether for HIV or even other pathogens," adds Schief.

With these promising data in hand spanning both safety and immune responses, the researchers will continue to iterate and design boosting immunogens that could eventually induce the desired bnAbs and provide protection against the virus. These findings also come shortly after two additionalstudies in Immunity published in September 2022, which helped validate the germline-targeting approach for vaccinating against HIV.

"Working together with IAVI, Scripps Research, the VRC, GWU, additional investigators at Fred Hutch and many others, this trial and additional analyses will help inform design of the remaining stages of a candidate HIV vaccine regimen -- while also enabling others in the field to develop vaccine strategies for additional viruses," says McElrath of Fred Hutch.

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Researchers seek to understand why vaccine responses vary from person to person

While vaccines are one of the most powerful public health tools for protecting against infectious disease, not everybody is conferred the same level of protection. Many factors determine whether an individual responding to vaccination will generate an effective response, including specific biomarkers within a person's immune system, but until now there has been no evidence showing whether these factors were universal across a wide range of vaccines.

New findings from a meta-analysis published in Nature Immunology examine the biological mechanisms responsible for why some people's immune systems respond differently to vaccinations, which could have global implications for the development and administration of vaccines.

As part of a series of studies for The Human Immunology Project Consortium (HIPC), a network of national research institutions studying the range of responses to different infections and vaccinations, Emory researchers analyzed the molecular characteristics of 820 healthy young adults who were immunized with 13 different vaccines to identify specific biomarkers that generate antibody response to vaccines.

The participants were separated into three endotypes, or groups with a common gene expression, based on the level of inflammatory response prior to vaccination -- a high inflammatory group, a low inflammatory group, and a mid-inflammatory group. After studying the immunological changes that occurred in participants following vaccination, researchers found the group that had the highest levels of inflammation prior to vaccine had the strongest antibody response.

"We were surprised because inflammation is usually depicted as something that is bad," says Slim Fourati, PhD, bioinformatic research associate at Emory University and first author on the paper. "These data indicate that some types of inflammation can actually foster a stronger response from a vaccine."

Fourati, Dr. Rafick-Pierre Sekaly, professor and senior author of the paper, and the HIPC team identified specific biomarkers among this group and cellular features that characterized the pre-vaccination inflammatory signature, information that can be used to predict how well an individual will respond to a vaccine.

"With the knowledge we now have about what characteristics of the immune system enable a more robust response, vaccines can be tailored to induce this response and maximize their effectiveness," says Fourati. "But we still have more questions to answer."

More research is needed to determine the cause of this inflammation in otherwise healthy adults. Additionally, Fourati suggests future studies should look at how these biomarkers facilitate vaccine protection in older age groups and among populations who are immunocompromised.

Published simultaneously with three other HIPC studies by researchers at Yale's School of Medicine, Stanford University, University of Cincinnati, Harvard Medical School, and Columbia University Medical Center, these findings can serve to improve vaccine response across all individuals. Better understanding of how various pre-vaccine immune states impact antibody responses opens the possibility of altering these states in more vulnerable individuals. For example, scientists may give patients predicted to have a weaker immune response an adjuvant with the vaccine to trigger the inflammatory genes associated with greater protection.

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SARS-CoV-2: Neutralization of BA.1 and BA.2 by therapeutic monoclonal antibodies

The SARS-CoV-2 Omicron BA.1 sublineage has been supplanted in many countries by the BA.2 sublineage. Although Omicron is responsible for less severe forms in the general population, immunocompromised people are still at higher risk of developing severe forms of COVID-19. Several monoclonal antibodies are currently available in clinical practice as a preventive treatment for these patients. Scientists from the Institut Pasteur, the CNRS, the Vaccine Research Institute (VRI), in collaboration with Orléans Regional Hospital, the Paris Public Hospital Network (AP-HP), KU Leuven (the Catholic University of Leuven) and Université Paris Cité, studied the sensitivity of Omicron BA.1 and BA.2 to nine monoclonal antibodies, some of which are used in pre-exposure prophylaxis in immunocompromised individuals. The scientists showed a loss of neutralizing activity against BA.1 and BA.2 in people treated with two antibody cocktails (Ronapreve® or Evusheld®). These findings were published in Nature Medicine on March 23, 2022.

The Omicron sublineage BA.2 has become increasingly common and is now dominant in several countries, including France. Scientists from the Institut Pasteur's Virus and Immunity Unit (a joint research unit with the CNRS) and the VRI began by studying the sensitivity of the Omicron BA.1 and BA.2 sublineages to therapeutic monoclonal antibodies in a cell culture system. This step involved isolating an infectious BA.2 strain in collaboration with the Rega Institute at KU Leuven. They then examined the efficacy of pre-exposure prophylaxis in immunocompromised individuals at risk of developing severe COVID-19. The scientists first described the in vitro sensitivity of BA.2 to nine therapeutic antibodies, as compared to the Delta variant and Omicron BA.1. They went on to examine the clinical implications of these observations by measuring the neutralizing activity of the antibodies in sera from 29 individuals who had been treated with Ronapreve® (a cocktail of two antibodies developed by Roche/Regeneron) and/or Evusheld® (a cocktail of two antibodies developed by AstraZeneca).

The scientists compared the ability of the patients' sera to tackle BA.1 and BA.2 between 3 and 30 days after treatment. The results of the study show that therapeutic sensitivity varies depending on the Omicron sublineage.

"We show that the antibodies and corresponding sera are inactive or only weakly active against BA.1, but more active against BA.2. As compared to the Delta variant, neutralizing titers were more markedly decreased against BA.1 (344-fold) than BA.2 (9-fold)," explained Timothée Bruel, lead author of the study and a scientist in the Virus and Immunity Unit at the Institut Pasteur (a joint research unit with the CNRS) with regard to Evusheld®.

Four Omicron infections were also reported among the 29 patients treated with antibodies (including one severe case). "This shows that, in this case, treatment does not fully protect against infection or against severe forms," explained Thierry Prazuck, co-last author of the study and Head of the Infectious Diseases Department at Orléans Regional Hospital.

"To our knowledge, this is the first study to directly describe the seroneutralization of individuals treated with monoclonal antibodies against Delta, BA.1 and BA.2, and to link the results with infections. BA.1, and to a lesser extent BA.2, is less sensitive to Evusheld® and Ronapreve® than Delta. This suggests that these treatments are probably less clinically effective against Omicron infection than against Delta," commented Olivier Schwartz, last author of the study and Head of the Virus and Immunity Unit at the Institut Pasteur (a joint research unit with the CNRS).

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Vaccine and antibody treatment effectiveness blunted by all three Omicron subvariants

Only one currently authorized antibody treatment retains its activity against all Omicron subvariants, according to new research by scientists at Columbia University and the University of Hong Kong. The study also shows that the effectiveness of mRNA vaccines is reduced against all three subvariants of Omicron.

The findings were published in Nature on March 2 by David D. Ho, MD, director of the Aaron Diamond AIDS Research Center and the Clyde'56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

Omicron is a highly transmissible variant of SARS-CoV-2 that has caused the biggest surge in COVID cases so far in many countries. Researchers have identified three subvariants of Omicron that share 21 mutations in the spike protein, and named them BA.1, BA.1.1 and BA.2.

When Omicron was first identified in November 2021, the dominant variant was BA.1. Since December, BA.1 cases have declined, while BA1.1 cases have risen and now make up around 40% of all Omicron cases sequenced globally. The BA.2 subvariant currently represents only 10% of all Omicron cases globally but is increasing in prevalence.

In laboratory experiments, Ho and his team studied the ability of 19 monoclonal antibodies and the sera from individuals immunized with one of two available mRNA vaccines to neutralize the three known subvariants of Omicron.

Consistent with their previous study on the BA.1 variant, the researchers observed a similar loss of neutralization activity against BA.1.1 and BA.2 in blood samples from individuals who had received two mRNA shots. However, the decline in neutralization was less prominent in blood samples from individuals who had received three mRNA shots, reinforcing the importance of booster shots for sustaining immunity.

In neutralization experiments, all three variants exhibited a strong resistance to most of the monoclonal antibodies tested. Of 19 antibodies, 17 were ineffective against the BA.2 subvariant. The researchers found that bebtelovimab, the latest monoclonal antibody to receive FDA Emergency Use Authorization, is the only currently available antibody therapy that can adequately treat all three Omicron subvariants.

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Researchers confirm newly developed inhaled vaccine delivers broad protection against SARS-CoV-2, variants of concern

Scientists at McMaster University who have developed an inhaled form of COVID vaccine have confirmed it can provide broad, long-lasting protection against the original strain of SARS-CoV-2 and variants of concern.

The research, recently published in the journal Cell, reveals the immune mechanisms and significant benefits of vaccines being delivered directly into the respiratory tract, rather than by traditional injection.

Because inhaled vaccines target the lungs and upper airways where respiratory viruses first enter the body, they are far more effective at inducing a protective immune response, the researchers report.

The reported preclinical study, which was conducted on animal models, has provided the critical proof of concept to enable a Phase 1 clinical trial that is currently under way to evaluate inhaled aerosol vaccines in healthy adults who had already received two doses of a COVID mRNA vaccine.

The tested COVID vaccine strategy was built upon a robust tuberculosis vaccine research program established by Zhou Xing, a co-lead author of the new study and a professor at the McMaster Immunology Research Centre and Department of Medicine.

"What we've discovered from many years' research is that the vaccine delivered into the lung induces all-around protective respiratory mucosal immunity, a property that the injected vaccine is lacking," Xing says.

Currently authorized COVID vaccines are all injected.

"We wanted, first and foremost, to design a vaccine that would work well against any variant," explains the study's co-lead author Matthew Miller, an associate professor at McMaster's Michael G. DeGroote Institute for Infectious Disease Research.

The McMaster COVID vaccine represents one of only a handful developed in Canada. The urgent work is a critical mission of Canada's Global Nexus for Pandemics and Biological Threats, which is based at McMaster.

Researchers compared two types of adenovirus platforms for the vaccine. The viruses serve as vectors that can deliver vaccine directly to the lungs without causing illness themselves.

"We can remain ahead of the virus with our vaccine strategy," says Miller. "Current vaccines are limited because they will need to be updated and will always be chasing the virus."

Both types of the new McMaster vaccine are effective against highly transmissible variants because they are designed to target three parts of the virus, including two that are highly conserved among coronaviruses and do not mutate as quickly as spike. All COVID vaccines currently approved in Canada target only the spike protein, which has shown a remarkable ability to mutate.

"This vaccine might also provide pre-emptive protection against a future pandemic, and that's really important because as we've seen during this pandemic -- and as we saw in 2009 with the swine flu -- even when we are able to rapidly make a vaccine for a pandemic virus, it's already way too late. Millions of people died, even though we were able to make a vaccine in record time," says Miller.

"We have revealed in our report that besides neutralizing antibodies and T cell immunity, the vaccine delivered into the lungs stimulates a unique form of immunity known as trained innate immunity, which is able to provide very broad protection against many lung pathogens besides SARS-CoV-2," Xing adds.

In additional to being needle and pain-free, an inhaled vaccine is so efficient at targeting the lungs and upper airways that it can achieve maximum protection with a small fraction of the dose of current vaccines -- possibly as little as 1 per cent -- meaning a single batch of vaccine could go 100 times further, the researchers say.

"This pandemic has shown us that vaccine supply can be a huge challenge. Demonstrating that this alternative delivery method can significantly extend vaccine supply could be a game changer, particularly in a pandemic setting," says Brian Lichty, an associate professor in the Department of Medicine who co-led the preclinical study along with Miller, Xing and the senior trainees Sam Afkhami and Michael D'Agostino, who are the joint first authors of the study.

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Vaccine protection against SARS-CoV-2 infection wanes quickly but is better maintained against severe disease, study finds

The vaccine-induced protection against SARS-CoV-2 infection wanes within a couple of months, but at different speed according to vaccine type. However, protection against severe COVID-19 appears to be better maintained. This is shown in a nationwide, registry-based study performed by researchers at Umeå University, Sweden, that now is published in The Lancet.

"The bad news is that the protection against infection seems to be diminished by seven months after the second dose of vaccine," says Peter Nordström, professor of geriatric medicine at Umeå University. "The good news, however, is that the protection against a severe infection that leads to hospitalization or death seems to be better maintained. Vaccination is therefore very wise and important."

The study, which received much attention once first posted as a 'preprint' in October, has now been peer-reviewed and the results as such confirmed. Following extensive revision and additional analyses, leading to results that more clearly show that the protection against severe COVID-19 seems better maintained than that against infection, the study has now been published in The Lancet.

The study is a nationwide, observational study based on registry-data from the Public Health Agency of Sweden, the National Board of Health and Welfare, and Statistics Sweden. The main analysis included almost 1.7 million individuals, and the results were confirmed in an even larger population of almost 4 million individuals. The results showed that protection against infection of any severity waned progressively following the peak which occurred a month after the second dose.

Six months after vaccination, the remaining protection against infection was 29 per cent from two doses of Pfizer, and 59 per cent from two doses of Moderna. There was no remaining protection from months and onwards for AstraZeneca. With respect to infections that were severe enough to warrant a hospital stay, or where the individual died within 30 days of confirmed infection, the protection was better maintained.

Protection against severe disease was 89 per cent after one month and 64 per cent from four months an onwards during the rest of the maximum follow-up of nine months. There was some evidence to suggest a lower protection in the oldest individuals and in individuals with homemaker service.

"The results underscore and support the decision to offer a third dose," says Marcel Ballin, doctoral student in geriatric medicine at Umeå University and co-author of the study. In particular, the results show that it was correct to prioritize the oldest and frailest individuals."

Prior to this study, a few observational studies and follow-up studies of the clinical trials have investigated waning vaccine protection in other countries. However, these have mostly covered the initial four to six months, and for the Pfizer vaccine.

"What this study contributes with is the longer follow-up time and the fact that we were able to explore how well the protection is maintained according to different types of vaccines," says Anna Nordström, adjunct professor in public health at Umeå University and co-author of the study.

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COVID-19 vaccines do not cause infertility, study finds

COVID-19 vaccination in either partner does not appear to affect fertility, according to new research led by Boston University School of Public Health (BUSPH) investigators.

Published in the American Journal of Epidemiology, the prospective study of couples trying to conceive found no association between COVID-19 vaccination and fecundability -- the probability of conception per menstrual cycle -- in female or male partners who received the Pfizer-BioNTech, Moderna, or Johnson & Johnson vaccines.

In contrast, the findings indicate that COVID-19 infection among males may temporarily reduce fertility -- an outcome that could be avoidable through vaccination.

"Many reproductive-aged individuals have cited concerns about fertility as a reason for remaining unvaccinated," says study lead author Dr. Amelia Wesselink, research assistant professor of epidemiology at BUSPH. "Our study shows for the first time that COVID-19 vaccination in either partner is unrelated to fertility among couples trying to conceive through intercourse. Time-to-pregnancy was very similar regardless of vaccination status."

Wesselink and colleagues analyzed survey data on COVID-19 vaccination and infection, and fecundability, among female and male participants in the BUSPH-based Pregnancy Study Online (PRESTO), an ongoing NIH-funded study that enrolls women trying to conceive, and follows them from preconception through six months after delivery. Participants included 2,126 women in the US and Canada who provided information on sociodemographics, lifestyle, medical factors, and characteristics of their partners from December 2020 to September 2021, and the participants were followed in the study through November 2021.

The researchers calculated the per menstrual cycle probability of conception using self-reported dates of participants' last menstrual period, typical menstrual cycle length, and pregnancy status. Fertility rates among female participants who received at least one dose of a vaccine were nearly identical to unvaccinated female participants. Fecundability was also similar for male partners who had received at least one dose of a COVID-19 vaccine compared with unvaccinated male participants. Additional analyses that considered the number of vaccine doses, brand of vaccine, infertility history, occupation, and geographic region also indicated no effect of vaccination on fertility.

While COVID-19 infection was not strongly associated with fertility, men who tested positive for COVID within 60 days of a given cycle had reduced fertility compared to men who never tested positive, or men who tested positive at least 60 days prior. This data supports previous research that has linked COVID-19 infection in men with poor sperm quality and other reproductive dysfunction.

"These data provide reassuring evidence that COVID vaccination in either partner does not affect fertility among couples trying to conceive," says study senior author Dr. Lauren Wise, professor of epidemiology at BUSPH. "The prospective study design, large sample size, and geographically heterogeneous study population are study strengths, as was our control for many variables such as age, socioeconomic status, preexisting health conditions, occupation, and stress levels."

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Researchers lay groundwork for potential dog-allergy vaccine

There have been many research efforts describing the nature and progression of dog allergies, but there have been very few applied studies that use this information to try to cure people of dog allergies entirely by artificially inducing immune tolerance. But researchers have now for the first time identified candidates for those parts of the molecules that make up dog allergens that could give us precisely that: a "dog allergy vaccine."

Their findings were published in the Federation of European Biochemical Societies journal on October 26.

Being allergic to dogs is a common malady and one that is growing worldwide. Over the years, scientists have been able to identify seven different dog allergens -- molecules or molecular structures that bind to an antibody and produce an unusually strong immune response that would normally be harmless.

These seven are named Canis familiaris allergens 1 to 7 (Can f 1-7). But while there are seven, just one, Can f 1, is responsible for the majority (50-75 percent) of reactions in people allergic to dogs. It is found in dogs' tongue tissue, salivary glands, and their skin.

Researchers have yet to identify Can f 1's IgE epitopes -- those specific parts of the antigens that are recognized by the immune system and stimulate or 'determine' an immune response (which is why epitopes are also called antigen determinants). More specifically, epitopes are short amino acid sequences making up part of a protein that induces the immune response.

Epitopes bind to a specific antigen receptor on the surface of immune system antibodies, B cells, or T Cells, much like how the shape of a jigsaw puzzle piece fits the specific shape of another puzzle piece. (The part of the receptor that binds to the epitope is in turn called a paratope). Antibodies, also known as immunoglobulin, come in five different classes or isotypes: IgA (for immunoglobulin A), IgD, IgE, IgG, or IgM. The IgE isotype (only found in mammals) plays a key role in allergies and allergic diseases. There is also an IgE epitope that is the puzzle piece that fits the IgE isotype's paratope.

In recent years, there has been extensive effort at developing epitope-focused vaccines -- in this case, a vaccine against dog allergies.

"We want to be able to present small doses of these epitopes to the immune system to train it to deal with them, similar to the principle behind any vaccine," said Takashi Inui, a specialist in allergy research, professor at Osaka Prefecture University and a lead author of the study. "But we can't do this without first identifying the Can f 1's IgE epitope."

So the researchers used X-ray crystallography (in which the diffraction of x-rays through a material is analyzed to identify its 'crystal' structure) to determine the structure of the Can f 1 protein as a whole -- the first time this had ever been done.

They found that the protein's folding pattern is at first glance extremely similar to three other Can f allergens. However, the locations of surface electrical charges were quite different, which in turn suggest a series of 'residues' that are good candidates for the IgE epitope.

Using this basic data, further experimental work needs to be performed to narrow the candidates down, but the findings suggest the development of a hypoallergenic vaccine against Can f 1 -- a dog-allergy vaccine -- is within our grasp.

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Scientists find new details about how immune system builds long-term memory

Experts in Japan have identified a fundamental part of the immune system's long-term memory, providing a useful new detail in the pursuit to design better vaccines for diseases, ranging from COVID-19 to malaria. The research, published in the Journal of Experimental Medicine, reveals a new role for the enzyme TBK1 in deciding the fate of immune system memory B cells.

The immune system is made of many cell types, but the two types relevant for this University of Tokyo research project are white blood cells called CD4+ follicular helper T cells and B cells. After the body recognizes an infection, the follicular helper T cells release chemical signals that cause immature B cells to learn and remember what pathogens to attack. This process of T-to-B cell signaling and B cell training occurs within a temporary cell structure called the germinal center in organs of the immune system, including the spleen, lymph nodes and tonsils. Memory B cells developed within the germinal center memorize a pathogen the first time it infects you and then if it ever gets into your body again, the mature, trained memory B cells attack it by inducing antibody production before the pathogen can multiply, saving you from feeling sick a second time.

"A goal of vaccination is to produce high-quality memory B cells for long-lasting antibody production," said Project Assistant Professor Michelle S. J. Lee from the UTokyo Institute of Medical Science, first author of the recent publication.

"There are many factors to consider when designing vaccines for long-lasting immunity, so we should not focus only on the germinal center alone. But if you don't have a functional germinal center, then you will be very susceptible to reinfection," said Lee.

However, there is no limit to the number of times you can be bitten by mosquitoes and reinfected by the malaria parasite. Somehow, malaria parasites escape memory B cells. Although children are more likely to die from malaria than adults, some people can become severely ill despite any number of previous malaria infections.

This ability of the parasite to prevent and evade effective B cells is what makes malaria an interesting pathogen for Professor Cevayir Coban, who leads the Division of Malaria Immunology at the UTokyo Institute of Medical Science and is last author of the research paper with Lee and collaborators at Osaka University.

"We want to understand the fundamentals of the natural immune response. Whatever we do should aim to eventually benefit malaria patients," said Coban. "The COVID-19 pandemic brought global attention to infectious diseases and interest in vaccine design, so we have a chance to renew the focus on neglected diseases like malaria," she continued.

Over many years, the scientific community has identified a wide range of roles for the molecule TBK1, an enzyme that can alter the activity of genes or other proteins by adding chemical tags, through a process called phosphorylation. TBK1 has well-known roles in antiviral immunity. However, no research group had connected TBK1 to B cell fate and the germinal center.

Researchers genetically modified mice that had nonfunctional TBK1 genes only in specific types of cells, primarily either B cells or CD4+ T cells. This cell type-specific knockout of TBK1 gives researchers a clearer idea of what a gene with many jobs is doing in different cells of the body. Coban, Lee and their colleagues infected these modified mice and healthy adult mice with the malaria parasite, observed their health, and then examined samples of their spleens and lymph nodes.

Microscopy images revealed that germinal centers only form in mice that have functional TBK1 in their B cells. Mice with no TBK1 in their B cells were more likely to die and died sooner from the malaria infection than their normal peers. Additional experiments showed that the few mice who survived malaria with no TBK1 in their B cells were able to use other types of immune responses, but they can become reinfected.

However, deleting TBK1 only from the CD4+ follicular helper T cells had no effect on the germinal centers or how the mice fared with a malaria infection.

Further analysis confirmed that without TBK1, many proteins in immature B cells had abnormal phosphorylation compared to normal immature B cells. For different genes, abnormal phosphorylation can cause either abnormal increases or decreases in activity. Researchers suspect that in B cells, TBK1 activity acts as an off switch for certain genes, essentially turning off genes that trap the B cells in their immature state.

"This is the first time to show TBK1 is essential in B cells to form the germinal centers and produce high-quality, mature antibodies," said Lee.

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Natural infection and vaccination together provide maximum protection against COVID variants

A combination of vaccination and naturally acquired infection appears to boost the production of maximally potent antibodies against the COVID-19 virus, new UCLA research finds.

The findings, published in the peer-reviewed journal mBio, raise the possibility that vaccine boosters may be equally effective in improving antibodies' ability to target multiple variants of the virus, including the delta variant, which is now the predominant strain, and the recently detected omicron variant. (The study was conducted prior to the emergence of delta and omicron, but Dr. Otto Yang, the study's senior author, said the results could potentially apply to those and other new variants.)

"The main message from our research is that someone who has had COVID and then gets vaccinated develops not only a boost in antibody amount, but also improved antibody quality -- enhancing the ability of antibodies to act against variants," said Yang, a professor of medicine in the division of infectious diseases and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA. "This suggests that having repeated exposures to the spike protein allows the immune system to continue improving the antibodies if someone had COVID then been vaccinated."

(The spike protein is the part of the virus that binds to cells, resulting in infection.)

Yang said it is not yet known whether the same benefits would be realized for people who have repeated vaccinations but who have not contracted COVID-19.

The researchers compared blood antibodies in 15 vaccinated people who had not been previously infected with SARS-CoV-2, the virus that causes COVID-19, with infection-induced antibodies in 10 people who were recently infected with SARS-CoV-2 but not yet vaccinated. Several months later, the 10 participants in the latter group were vaccinated, and the researchers then reanalyzed their antibodies. Most people in both of the groups had received the Pfizer-BioNTech or Moderna two-dose vaccines.

The scientists evaluated how antibodies acted against a panel of spike proteins with various common mutations in the receptor-binding domain, which is the target for antibodies that help neutralize the virus by blocking it from binding to cells.

They found that the receptor-binding domain mutations reduced the potency of antibodies acquired both by either natural infection or vaccination alone, to about the same degree in both groups of people. When previously infected people were vaccinated about a year after natural infection, however, their antibodies' potency was maximized to a point that they recognized all of the COVID-19 variants the scientists tested.

"Overall, our findings raise the possibility that resistance of SARS-CoV-2 variants to antibodies can be overcome by driving further maturation through continued antigenic exposure by vaccination, even if the vaccine does not deliver variant sequences," the researchers write. They suggest that repeated vaccinations may have the capacity to accomplish the same thing as getting vaccinated after having had COVID-19, although further research will be required to address that possibility.

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Immune system-stimulating nanoparticle could lead to more powerful vaccines

A common strategy to make vaccines more powerful is to deliver them along with an adjuvant -- a compound that stimulates the immune system to produce a stronger response.

Researchers from MIT, the La Jolla Institute for Immunology, and other institutions have now designed a new nanoparticle adjuvant that may be more potent than others now in use. Studies in mice showed that it significantly improved antibody production following vaccination against HIV, diphtheria, and influenza.

"We started looking at this particular formulation and found that it was incredibly potent, better than almost anything else we had tried," says Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT's departments of Biological Engineering and Materials Science and Engineering; an associate director of MIT's Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard.

The researchers now hope to incorporate the adjuvant into an HIV vaccine that is currently being tested in clinical trials, in hopes of improving its performance.

Irvine and Shane Crotty, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology, are the senior authors of the study, which appears today in Science Immunology. The lead authors of the paper are Murillo Silva, a former MIT postdoc, and Yu Kato, a staff scientist at the La Jolla Institute.

More powerful vaccines

Although the idea of using adjuvants to boost vaccine effectiveness has been around for decades, there are only a handful of FDA-approved vaccine adjuvants. One is aluminum hydroxide, an aluminum salt that induces inflammation, and another is an oil and water emulsion that is used in flu vaccines. A few years ago, the FDA approved an adjuvant based on saponin, a compound derived from the bark of the Chilean soapbark tree.

Saponin formulated in liposomes is now used as an adjuvant in the shingles vaccine, and saponins are also being used in a cage-like nanoparticle called an immunostimulatory complex (ISCOM) in a Covid-19 vaccine that is currently in clinical trials.

Researchers have shown that saponins promote inflammatory immune responses and stimulate antibody production, but how they do that is unclear. In the new study, the MIT and La Jolla team wanted to figure out how the adjuvant exerts its effects, and to see if they could make it more potent.

They designed a new type of adjuvant that is similar to the ISCOM adjuvant but also incorporates a molecule called MPLA, which is a toll-like receptor agonist. When these molecules bind to toll-like receptors on immune cells, they promote inflammation. The researchers call their new adjuvant SMNP (saponin/MPLA nanoparticles).

"We expected that this could be interesting because saponin and toll-like receptor agonists are both adjuvants that have been studied separately and shown to be very effective," Irvine says.

The researchers tested the adjuvant by injecting it into mice along with a few different antigens, or fragments of viral proteins. These included two HIV antigens, as well as diphtheria and influenza antigens. They compared the adjuvant to several other approved adjuvants and found that the new saponin-based nanoparticle elicited a stronger antibody response than any of the others.

One of the HIV antigens that they used is an HIV envelope protein nanoparticle, which presents many copies of the gp120 antigen that is present on the HIV viral surface. This antigen recently completed initial testing in phase 1 clinical trials. Irvine and Crotty are part of the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute, which ran that trial. The researchers now hope to develop a way to manufacture the new adjuvant at large scale so it can be tested along with an HIV envelope trimer in another clinical trial beginning next year. Clinical trials that combine envelope trimers with the traditional vaccine adjuvant aluminum hydroxide are also underway.

"Aluminum hydroxide is safe but not particularly potent, so we hope that (the new adjuvant) would be an interesting alternative to elicit neutralizing antibody responses in people," Irvine says.

Rapid flow

When vaccines are injected into the arm, they travel through lymph vessels to the lymph nodes, where they encounter and activate B cells. The research team found that the new adjuvant speeds up the flow of lymph to the nodes, helping the antigen to get there before it starts to break down. It does this in part by stimulating immune cells called mast cells, which previously were not known to be involved in vaccine responses.

"Getting to the lymph nodes quickly is useful because once you inject the antigen, it starts slowly breaking down. The sooner a B cell can see that antigen, the more likely it's fully intact, so that B cells are targeting the structure as it will be present on the native virus," Irvine says.

Additionally, once the vaccine reaches the lymph nodes, the adjuvant causes a layer of cells called macrophages, which act as a barrier, to die off quickly, making it easier for the antigen to get into the nodes.

Another way that the adjuvant helps boost immune responses is by activating inflammatory cytokines that drive a stronger response. The TLR agonist that the researchers included in the adjuvant is believed to amplify that cytokine response, but the exact mechanism for that is not known yet.

This kind of adjuvant could also be useful for any other kind of subunit vaccine, which consists of fragments of viral proteins or other molecules. In addition to their work on HIV vaccines, the researchers are also working on a potential Covid-19 vaccine, along with J. Christopher Love's lab at the Koch Institute. The new adjuvant also appears to help stimulate T cell activity, which could make it useful as a component of cancer vaccines, which aim to stimulate the body's own T cells to attack tumors.

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DNA tangles can help predict evolution of mutations

Tangles in unwound DNA can create mutational hotspots in the genomes of bacteria, according to a new study by the Milner Centre for Evolution at the University of Bath. The study authors say these findings will help us in the future to predict the evolution of bacteria and viruses over time, which could aid vaccine design and better understanding of antibiotic resistance.

While most evolution is shaped by natural selection, where only those individuals who are adapted for their environment are able to survive and pass on their genes, a new study published in Nature Communications shows that evolution is also influenced by tangles in the DNA strands.

A team of scientists, led by the University of Bath in collaboration with the University of Birmingham, looked at the evolution of two strains of the soil bacteria Pseudomonas fluorescens (SBW25 and Pf0-1).

When the scientists removed a gene that enables the bacteria to swim, both strains of the bacteria quickly evolved the ability to swim again, but using quite different routes.

One of the strains (called SBW25), always mutated the same part of a particular gene to regain mobility.

However, the other strain (called Pf0-1) mutated different places in different genes each time the scientists repeated the experiment.

To understand why one strain evolved predictably and the other was unpredictable, they compared the DNA sequences of the two strains. They found that in the SBW25 strain, which mutated in a predictable way, there was a region where the DNA strand looped back on itself forming a hairpin-shaped tangle.

These tangles can disrupt the cell machinery, called DNA polymerase, which copies the gene during cell division, and so makes mutations more likely to happen.

When the team removed the hairpin structure using six silent mutations (without changing the sequence of the protein produced), this abolished the mutational hotspot and the bacteria started evolving in a much wider variety of ways to get back its swimming ability.

Dr Tiffany Taylor, from the Milner Centre for Evolution, said: "DNA normally forms a double helix structure, but when the DNA is copied, the strands are briefly separated.

"We've found there are hotspots in the DNA where the sequence causes the separated strands of DNA to get twisted back on themselves -- a bit like when you pull apart the strands of a rope -- this results in a tangle.

"When the DNA polymerase enzyme runs along the strand to copy the gene, it bumps into the tangle and can skip, causing a mutation.

"Our experiments show that we were able to create or remove mutational hotspots in the genome by altering the sequence to cause or prevent the hairpin tangle.

"This shows that while natural selection is still the most important factor in evolution, there are other factors at play too.

"If we knew where the potential mutational hotspots in bacteria or viruses were, it might help us to predict how these microbes could mutate under selective pressure."

Mutational hotspots have already been found in cancer cells, and the researchers plan to search for them across a range of bacterial species, including important pathogens.

This information can help scientists better understand how bacteria and viruses evolve, which can help in developing vaccines against new variants of diseases. It can also make it easier to predict how microbes might develop resistance to antibiotics.

Dr James Horton, who has recently completed his PhD at the Milner Centre for Evolution, said: "Like many exciting discoveries, this was found by accident. The mutations we were looking at were so-called silent because they don't change the resulting protein sequence, so initially we didn't think they were particularly important.

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Allergies to mRNA-based COVID-19 vaccines rare, generally mild, study finds

Allergic reactions to the new mRNA-based COVID-19 vaccines are rare, typically mild and treatable, and they should not deter people from becoming vaccinated, according to research from the Stanford University School of Medicine.

The findings will be published online Sept. 17 in JAMA Network Open.

"We wanted to understand the spectrum of allergies to the new vaccines and understand what was causing them," said the study's senior author, Kari Nadeau, MD, PhD, the Naddisy Foundation Professor in Pediatric Food Allergy, Immunology, and Asthma.

The study analyzed 22 potential allergic reactions to the first 39,000 doses of Pfizer and Moderna COVID-19 vaccines given to health care providers at Stanford soon after the vaccines received emergency use authorization from the Food and Drug Administration.

Most of those in the study who developed reactions were allergic to an ingredient that helps stabilize the COVID-19 vaccines; they did not show allergies to the vaccine components that provide immunity to the SARS-CoV-2 virus. Furthermore, these allergic reactions occurred via an indirect activation of allergy pathways, which makes them easier to mitigate than many allergic responses.

"It's nice to know these reactions are manageable," said Nadeau, who directs the Sean N. Parker Center for Allergy and Asthma Research at Stanford. "Having an allergic reaction to these new vaccines is uncommon, and if it does happen, there's a way to manage it."

The study's lead author is former postdoctoral scholar Christopher Warren, PhD, now an assistant professor at Northwestern University Feinberg School of Medicine.

The research also suggests how vaccine manufacturers can reformulate the vaccines to make them less likely to trigger allergic responses, Nadeau said.

Delivery of protein-making instructions

The mRNA-based COVID-19 vaccines provide immunity via small pieces of messenger RNA that encode molecular instructions for making proteins. Because the mRNA in the vaccines is fragile, it is encased in bubbles of lipids -- fatty substances -- and sugars for stability. When the vaccine is injected into someone's arm, the mRNA can enter nearby muscle and immune cells, which then manufacture noninfectious proteins resembling those on the surface of the SARS-CoV-2 virus. The proteins trigger an immune response that allows the person's immune system to recognize and defend against the virus.

Estimated rates of severe vaccine-related anaphylaxis -- allergic reactions bad enough to require hospitalization -- are 4.7 and 2.5 cases per million doses for the Pfizer and Moderna vaccines, respectively, according to the federal Vaccine Adverse Event Reporting System. However, the federal system doesn't capture all allergic reactions to vaccines, tending to miss those that are mild or moderate.

For a more complete understanding of allergic reactions to the new vaccines -- how common they are, as well as how severe -- the research team examined the medical records of health care workers who received 38,895 doses of mRNA-based COVID-19 vaccines at Stanford Medicine between Dec. 18, 2020, and Jan. 26, 2021. The vaccinations included 31,635 doses of the Pfizer vaccine and 7,260 doses of the Moderna vaccine.

The researchers searched vaccine recipients' medical records for treatment of allergic reactions and identified which reactions were linked to the vaccines. Twenty-two recipients, 20 of them women, had possible allergic reactions, meaning specific symptoms starting within three hours of receiving the shots. The researchers looked for the following symptoms in recipients' medical records: hives; swelling of the mouth, lips, tongue or throat; shortness of breath, wheezing or chest tightness; or changes in blood pressure or loss of consciousness. Only 17 of the 22 recipients had reactions that met diagnostic criteria for an allergic reaction. Three recipients received epinephrine, usually given for stronger anaphylaxis. All 22 fully recovered.

Of the 22 recipients, 15 had physician-documented histories of prior allergic reactions, including 10 to antibiotics, nine to foods and eight to nonantibiotic medications. (Some recipients had more than one type of allergy.)

The researchers performed follow-up laboratory testing on 11 individuals to determine what type of allergic reaction they had, as well as what triggered their allergy: Was it one of the inert sugar or lipid ingredients in the bubble, or something else in the vaccine?

The study participants underwent skin-prick tests, in which a clinician injected small amounts of potential allergens -- the lipids, sugars (polyethylene glycol or polysorbates) or entire vaccine -- into the skin. Skin-prick testing detects allergic reactions mediated by a form of antibody known as immunoglobin E, or IgE; these reactions are generally associated with the severest allergies.

None of the recipients reacted on skin-prick tests to the inert ingredients in the vaccines, and just one recipient's skin reacted to the whole COVID-19 vaccine. Follow-up blood tests showed that the vaccine recipients did not have significant levels of IgE antibodies against the vaccine ingredients.

Since the skin tests did not explain the mechanism of recipients' allergic reactions, the investigators proceeded to another type of diagnostic test. Vaccine recipients provided blood samples for tests of allergic activation of immune cells known as basophils. The blood samples from 10 of the 11 participants showed a reaction to the inert ingredient polyethylene glycol (PEG), which is used in both the Pfizer and Moderna vaccines. In addition, all 11 recipients had basophil activation in response to the whole mRNA vaccine when it was mixed with their own basophils.

All 11 subjects had high levels of IgG antibodies against PEG in their blood; IgG antibodies help activate basophils under some conditions, and this finding suggests the individuals were likely sensitive to PEG before receiving their vaccines.

"What's important is what we didn't find, as much as what we did find," Nadeau said. "It does not seem that the mRNA itself causes the allergic reactions."

In addition, the data suggest that reactions to the COVID-19 vaccines were generally not the most severe form of allergic reaction, which is good news in terms of vaccine safety, she said. Allergic reactions mediated by IgG and basophils can be managed with antihistamines, fluids, corticosteroids and close observation, meaning that many individuals who have had a reaction to their first vaccine dose can safely receive a second dose under medical supervision.

PEG is widely used as a stabilizer in household products, cosmetics and medications, with women more likely to be exposed to large quantities of the substance, possibly explaining why more vaccine allergies have been seen among women. (Repeated exposures to a substance can sometimes sensitize the immune system and provoke allergies.) Because most reactions were to PEG rather than the vaccine's active ingredients, it is likely that vaccine manufacturers can reformulate the vaccines with different stabilizers that are less likely to cause allergies, Nadeau said.

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COVID-19 nasal vaccine candidate effective at preventing disease transmission, study shows

Breathe in, breathe out. That's how easy it is for SARS-CoV-2, the virus that causes COVID-19, to enter your nose. And though remarkable progress has been made in developing intramuscular vaccines against SARS-CoV- 2, such as the readily available Pfizer, Moderna and Johnson & Johnson vaccines, nothing yet -- like a nasal vaccine -- has been approved to provide mucosal immunity in the nose, the first barrier against the virus before it travels down to the lungs.

But now, we're one step closer.

Navin Varadarajan, University of Houston M.D. Anderson Professor of Chemical and Biomolecular Engineering, and his colleagues, are reporting in iScience the development of an intranasal subunit vaccine that provides durable local immunity against inhaled pathogens.

"Mucosal vaccination can stimulate both systemic and mucosal immunity and has the advantage of being a non-invasive procedure suitable for immunization of large populations," said Varadarajan. "However, mucosal vaccination has been hampered by the lack of efficient delivery of the antigen and the need for appropriate adjuvants that can stimulate a robust immune response without toxicity."

To solve those problems, Varadarajan collaborated with Xinli Liu, associate professor of pharmaceutics at the UH College of Pharmacy, and an expert in nanoparticle delivery. Liu's team was able to encapsulate the agonist of the stimulator of interferon genes (STING) within liposomal particles to yield the adjuvant named NanoSTING. The function of the adjuvant is to promote the body's immune response.

"NanoSTING has a small particle size around 100 nanometers which exhibits significantly different physical and chemical properties to the conventional adjuvant," said Liu.

"We used NanoSTING as the adjuvant for intranasal vaccination and single-cell RNA-sequencing to confirm the nasal-associated lymphoid tissue as an inductive site upon vaccination. Our results show that the candidate vaccine formulation is safe, produces rapid immune responses -- within seven days -- and elicits comprehensive immunity against SARS-CoV-2," said Varadarajan.

A fundamental limitation of intramuscular vaccines is that they are not designed to elicit mucosal immunity. As prior work with other respiratory pathogens like influenza has shown, sterilizing immunity to virus re-infection requires adaptive immune responses in the respiratory tract and the lung.

The nasal vaccine will also serve to equitably distribute vaccines worldwide, according to the researchers. It is estimated that first world countries have already secured and vaccinated multiple intramuscular doses for each citizen while billions of people in countries like India, South Africa, and Brazil with large outbreaks are currently unimmunized. These outbreaks and viral spread are known to facilitate viral evolution leading to decreased efficacy of all vaccines.

"Equitable distribution requires vaccines that are stable and that can be shipped easily. As we have shown, each of our components, the protein (lyophilized) and the adjuvant (NanoSTING) are stable for over 11 months and can be stored and shipped without the need for freezing," said Varadarajan.

Varadarajan is co-founder of AuraVax Therapeutics Inc., a pioneering biotech company developing novel intranasal vaccines and therapies to help patients defeat debilitating diseases, including COVID-19. The company has an exclusive license agreement with UH with respect to the intellectual property covering intranasal vaccines and STING agonist technologies. They have initiated the manufacturing process and plan to engage the FDA later this year.

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With time and without masks, COVID-19 vaccines wane in protection, study finds

In a letter to The New England Journal of Medicine, publishing online September 1, 2021, an interdisciplinary team of physicians and public health experts at University of California San Diego measured the effectiveness of COVID-19 mRNA vaccines among health workers at UC San Diego Health, most notably during the emergence of the highly transmissible delta virus variant and coincident with the end of the state's mask mandate, allowing fully vaccinated persons to forgo face coverings in most places.

The letter's authors report that the effectiveness of both the Pfizer and Moderna mRNA COVID-19 vaccines significantly waned over time. Both vaccines were granted emergency use authorization by the Food and Drug Administration in December 2020, with vaccinations of the UC San Diego Health work force beginning the same month for health care workers with direct, patient-facing duties.

In the letter, the authors note that from March through June 2021 vaccine effectiveness against symptomatic infection was estimated to exceed 90 percent; by July, however, it had fallen to approximately 65 percent.

"The decline in effectiveness is not entirely surprising," said co-senior author Francesca Torriani, MD, professor of clinical medicine in the Division of Infectious Diseases and Global Public Health in the UC San Diego School of Medicine and program director of Infection Prevention and Clinical Epidemiology at UC San Diego Health.

"Clinical trial data suggested decreased effectiveness would occur several months after full vaccination, but our findings indicate that confronted by the delta variant, vaccine effectiveness for mildly symptomatic disease was considerably lower and waned six to eight months after completing vaccination."

UC San Diego Health, with a work force of approximately 19,000, operates a robust SARS-CoV-2 testing program. If an employee reports even one mild symptom of COVID-19 during daily screening or an identified exposure, a test is triggered.

Then and now, UC San Diego Health has maintained rigorous, mandatory masking and transmission mitigation measures throughout its hospitals and clinical facilities. Diagnosed positive cases among health workers have universally been identified as community acquired.

In December 2020, workers at UC San Diego Health, like the population overall, began experiencing a surge of SARS-CoV-2 infections, the virus that causes COVID-19.

The situation improved significantly after UC San Diego Health began to inoculate employees using the Pfizer and Moderna vaccines. By March 2021, 76 percent of workers were fully vaccinated, rising to 83 percent by July 2021.

Concomitant with increased vaccination coverage was a decline between March and June in the number of workers reporting at least one symptom of COVID-19 and a positive PCR test. That number declined to fewer than 30 employees per month.

In July 2021, however, cases among this highly vaccinated population began to rise again, coincident with the emerging dominance of the delta variant in San Diego and the ending of California's masking mandate on June 15. By July, 125 workers had been diagnosed with SARS-CoV-2 and unlike in previous months when approximately 20 percent of these cases involved vaccinated workers, the percentage had risen to 75 percent.

Notably, the vaccines still provide significant protection from severe infection outcomes, such as hospitalization and death. Among the UC San Diego Health employee cases documented, no hospitalizations were reported in vaccinated individuals and only one among unvaccinated persons.

"Unlike what was experienced with other variants, with the delta variant parents are frequently getting infected by their young children, ages 5 to 11," said co-first author Lucy Horton, MD, MPH, an assistant professor of medicine in the Division of Infectious Diseases and director of the UC San Diego Health COVID-19 case investigation and contact tracing team. "Unvaccinated people are seven times more likely to test positive for COVID-19 than those who are fully vaccinated. More importantly, while children rarely need medical attention, unvaccinated adults are 32 times more likely to require hospitalization compared to those who are fully vaccinated."

Vaccine effectiveness was linked to the passage of time. For workers diagnosed in July, those who became fully vaccinated in January and February had higher infection rates than those vaccinated later in March through May. The infection rate among unvaccinated persons has remained consistently higher than for any vaccinated group, although the difference in rates between the two groups has decreased over time.

"The dramatic change in vaccine effectiveness from June to July is likely due to a combination of factors," said co-author Nancy Binkin, MD, MPH, professor of epidemiology in the UC San Diego School of Medicine and Herbert Wertheim School of Public Health and Human Longevity Science. "It's the emergence of the delta variant and waning immunity over time, compounded by the end of broad masking requirements and the resulting greater exposure risk throughout the community."

Co-senior author Shira Abeles, MD, an assistant professor of medicine in the Division of Infectious Diseases who has led the COVID-19 vaccination effort at UC San Diego Health, said the findings underscore the importance of rapidly reinstating key interventions, such as indoor masking and intensive testing strategies, plus continuing efforts to boost vaccination rates.

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