Several years ago, MIT researchers showed that administering a series of escalating doses of an HIV vaccine over a two-week period could help overcome a part of that challenge by generating larger quantities of neutralizing antibodies. However, a multidose vaccine regimen administered over a short time is not practical for mass vaccination campaigns.

In a new study, the researchers have now found that they can achieve a similar immune response with just two doses, given one week apart. The first dose, which is much smaller, prepares the immune system to respond more powerfully to the second, larger dose.

This study, which was performed by bringing together computational modeling and experiments in mice, used an HIV envelope protein as the vaccine. A single-dose version of this vaccine is now in clinical trials, and the researchers hope to establish another study group that will receive the vaccine on a two-dose schedule.

“By bringing together the physical and life sciences, we shed light on some basic immunological questions that helped develop this two-dose schedule to mimic the multiple-dose regimen,” says Arup Chakraborty, the John M. Deutch Institute Professor at MIT and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH and Harvard University.

This approach may also generalize to vaccines for other diseases, Chakraborty notes.

Chakraborty and Darrell Irvine, a former MIT professor of biological engineering and materials science and engineering and member of the Koch Institute for Integrative Cancer Research, who is now a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the study, which appears in Science Immunology. The lead authors of the paper are Sachin Bhagchandani PhD ’23 and Leerang Yang PhD ’24.

Neutralizing antibodies

Each year, HIV infects more than 1 million people around the world, and some of those people do not have access to antiviral drugs. An effective vaccine could prevent many of those infections. One promising vaccine now in clinical trials consists of an HIV protein called an envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by Irvine’s lab, acts as an adjuvant that helps recruit a stronger B cell response to the vaccine.

In clinical trials, this vaccine and other experimental vaccines have been given as just one dose. However, there is growing evidence that a series of doses is more effective at generating broadly neutralizing antibodies. The seven-dose regimen, the researchers believe, works well because it mimics what happens when the body is exposed to a virus: The immune system builds up a strong response as more viral proteins, or antigens, accumulate in the body.

In the new study, the MIT team investigated how this response develops and explored whether they could achieve the same effect using a smaller number of vaccine doses.

“Giving seven doses just isn’t feasible for mass vaccination,” Bhagchandani says. “We wanted to identify some of the critical elements necessary for the success of this escalating dose, and to explore whether that knowledge could allow us to reduce the number of doses.”

The researchers began by comparing the effects of one, two, three, four, five, six, or seven doses, all given over a 12-day period. They initially found that while three or more doses generated strong antibody responses, two doses did not. However, by tweaking the dose intervals and ratios, the researchers discovered that giving 20 percent of the vaccine in the first dose and 80 percent in a second dose, seven days later, achieved just as good a response as the seven-dose schedule.

“It was clear that understanding the mechanisms behind this phenomenon would be crucial for future clinical translation,” Yang says. “Even if the ideal dosing ratio and timing may differ for humans, the underlying mechanistic principles will likely remain the same.”

Using a computational model, the researchers explored what was happening in each of these dosing scenarios. This work showed that when all of the vaccine is given as one dose, most of the antigen gets chopped into fragments before it reaches the lymph nodes. Lymph nodes are where B cells become activated to target a particular antigen, within structures known as germinal centers.

When only a tiny amount of the intact antigen reaches these germinal centers, B cells can’t come up with a strong response against that antigen.

However, a very small number of B cells do arise that produce antibodies targeting the intact antigen. So, giving a small amount in the first dose does not “waste” much antigen but allows some B cells and antibodies to develop. If a second, larger dose is given a week later, those antibodies bind to the antigen before it can be broken down and escort it into the lymph node. This allows more B cells to be exposed to that antigen and eventually leads to a large population of B cells that can target it.

“The early doses generate some small amounts of antibody, and that’s enough to then bind to the vaccine of the later doses, protect it, and target it to the lymph node. That’s how we realized that we don’t need to give seven doses,” Bhagchandani says. “A small initial dose will generate this antibody and then when you give the larger dose, it can again be protected because that antibody will bind to it and traffic it to the lymph node.”

T-cell boost

Those antigens may stay in the germinal centers for weeks or even longer, allowing more B cells to come in and be exposed to them, making it more likely that diverse types of antibodies will develop.

The researchers also found that the two-dose schedule induces a stronger T-cell response. The first dose activates dendritic cells, which promote inflammation and T-cell activation. Then, when the second dose arrives, even more dendritic cells are stimulated, further boosting the T-cell response.

Overall, the two-dose regimen resulted in a fivefold improvement in the T-cell response and a 60-fold improvement in the antibody response, compared to a single vaccine dose.

“Reducing the ‘escalating dose’ strategy down to two shots makes it much more practical for clinical implementation. Further, a number of technologies are in development that could mimic the two-dose exposure in a single shot, which could become ideal for mass vaccination campaigns,” Irvine says.

The researchers are now studying this vaccine strategy in a nonhuman primate model. They are also working on specialized materials that can deliver the second dose over an extended period of time, which could further enhance the immune response.

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.

Written by Anne Trafton, MIT News

The results of the ELVIS-Kids randomised controlled trial were presented by Professor Steve Cunningham from Child Life and Health, University of Edinburgh, UK.

He said: “Children have up to 10 to 12 upper respiratory tract infections, what we refer to as colds, per year, which have a big impact on them and their families. There are medicines to improve symptoms, such as paracetamol and ibuprofen, but no treatments that can make a cold get better quicker.”

ELVIS-Kids Chief Investigator Dr Sandeep Ramalingam, consultant virologist, NHS Lothian, Edinburgh, UK, had noted that salt-water solutions are often used by people in South Asia, as nasal irrigation and gargling, to treat a cold and wanted to explore if this clinical benefit could be replicated in a large study.

The research team recruited 407 children aged up to six years to a study where they were given either hypertonic saline ~2.6% (salt-water) nasal drops or usual care when they developed a cold. Overall, 301 children developed a cold; for 150 of these, their parents were given sea salt and taught to make and apply salt-water nose drops to the children’s noses (three drops per nostril, a minimum of four times per day, until well) and 151 children had usual cold care.

Professor Cunningham explains: “We found that children using salt-water nose drops had cold symptoms for an average of six days where those with usual care had symptoms for eight days. The children receiving salt water nose drops also needed fewer medicines during their illness.

“Salt is made up of sodium and chloride. Chloride is used by the cells lining the nose and windpipes to produce hypochlorous acid within cells, which they use to defend against virus infection. By giving extra chloride to the lining cells this helps the cells produce more hypochlorous acid, which helps suppress viral replication, reducing the length of the virus infection, and therefore the duration of symptoms.”

When children got salt-water nose drops, fewer households reported family members catching a cold (46% vs 61% for usual care). Eighty-two per cent of parents said the nose drops helped the child get better quickly and 81% said they would use nose drops in the future.

Professor Cunningham added: “Reducing the duration of colds in children means that fewer people in their house also get a cold, with clear implications for how quickly a household feels better and can return to their usual activities like school and work etc.

“Our study also showed that parents can safely make and administer nose drops to their children and therefore have some control over the common cold affecting their children.”

Professor Alexander Möeller is Head of the ERS Paediatric Assembly and Head of the Department for Respiratory Medicine at the University Children’s Hospital Zurich, Switzerland, and was not involved in the research. He said: “This is an important study that is the first of its kind to investigate the impact of salty nose drops in children with colds. Although most colds usually don’t turn into anything serious, we all know how miserable they can be, especially for young children and their families.

“This extremely cheap and simple intervention has the potential to be applied globally; providing parents with a safe and effective way to limit the impact of colds in their children and family would represent a significant reduction in health and economic burden of this most common condition.”

The team hope to further investigate the effect of saltwater nose drops on wheeze during colds, after initial results from this study showed that children who received the drops had significantly fewer episodes of wheeze (5% vs 19%).

The five-year, multi-center study is funded by a $9.2 million National Institutes of Health grant and will compare the effectiveness of a recently approved medication, secnidazole, against the current standard treatment, metronidazole, using a 1,200-person cohort across Louisiana, Alabama and Florida. Despite decades of use as the primary trichomoniasis medication, treatment by metronidazole continues to have a 10% breakthrough rate.

“More than 10 percent of people who take the recommended treatment still have it. That is just unacceptable. We need better options” said Dr. Patty Kissinger, professor of epidemiology at Tulane School of Public Health and Tropical Medicine. “The problem is trichomoniasis is the most common treatable STI, but there are often no symptoms, and the CDC has not recommended screening among asymptomatic people, so the public doesn’t know about it.”

Trichomoniasis, which infects about 156 million people annually worldwide, is caused by trichomonas vaginalis, a parasite that thrives in the genital tract of both men and women and causes inflammation. Those infected have a 1.5 times higher susceptibility to HIV. For expecting mothers, it can cause pre-term birth and increase risk for perinatal morbidity. African American women are also four times more likely to have trichomoniasis.

“Trichomoniasis affects millions but remains a highly neglected STI,” Kissinger said. “We’re hoping this study leads to better treatment options and increased awareness that we hope will encourage more screening.”

Because of the lack of inclusion in STI screenings and scant symptoms, those infected can go years before realizing they have trichomoniasis.

This is the third in a series of studies funded by the NIH to refine treatment for trichomoniasis. This is the first study in the series to include men in its cohort and the first-ever study to compare the effectiveness of secnidazole with metronidazole.

Questions remain as to why metronidazole continues to have a high breakthrough rate. The prior NIH studies found that metronidazole is most effective when administered in multiple doses, but the breakthrough rate may be attributed to patients missing doses or having sex with partners before treatment is completed, creating a cycle of reinfection.

The secnidazole treatment would only require one dose, although some concerns remain about the cost of the medication, Kissinger said.

Trichomoniasis affects more than 3 million people in the United States and is particularly prevalent in the Deep South where the study is being conducted.

“We need better treatments for this STI,” Kissinger said. “If this is successful, we could control it and encourage more screening that could reduce perinatal morbidity and maybe even reduce the chances of some people getting HIV.”

The study, published in JRSM Open, analysed data from over 1,000 people in England and Wales who logged their symptoms on an app between November 2020 and March 2022.

Pain, including headache, joint pain and stomach pain, was the most common symptom, reported by 26.5% of participants.

The other most common symptoms were neuropsychological issues such as anxiety and depression (18.4%), fatigue (14.3%), and dyspnoea (shortness of breath) (7.4%). The analysis found that the intensity of symptoms, particularly pain, increased by 3.3% on average each month since initial registration.

The study also examined the impact of demographic factors on the severity of symptoms, revealing significant disparities among different groups. Older individuals were found to experience much higher symptom intensity, with those aged 68-77 reporting 32.8% more severe symptoms, and those aged 78-87 experiencing an 86% increase in symptom intensity compared to the 18-27 age group.

Gender differences were also pronounced, with women reporting 9.2% more intense symptoms, including pain, than men. Ethnicity further influenced symptom severity, as non-white individuals with long Covid reported 23.5% more intense symptoms, including pain, compared to white individuals.

The study also explored the relationship between education levels and symptom severity. Individuals with higher education qualifications (NVQ level 3, 4, and 5 – equivalent to A-levels or higher education) experienced significantly less severe symptoms, including pain, with reductions of 27.7%, 62.8%, and 44.7% for NVQ levels 3, 4 and 5 respectively, compared to those with lower education levels (NVQ level 1-2 – equivalent to GCSEs).

Socioeconomic status, as measured by the Index of Multiple Deprivation (IMD), also influenced symptom intensity. Participants from less deprived areas reported less intense symptoms than those from the most deprived areas. However, the number of symptoms did not significantly vary with socioeconomic status, suggesting that while deprivation may exacerbate symptom intensity, it does not necessarily lead to a broader range of symptoms.

Lead author Dr David Sunkersing (UCL Institute of Health Informatics) said: “Our study highlights pain as a predominant self-reported symptom in long Covid, but it also shows how demographic factors appear to play a significant role in symptom severity.

“With ongoing occurrences of Covid-19 (e.g., LB.1, or D-FLiRT variants), the potential for more long Covid cases remains a pressing concern. Our findings can help shape targeted interventions and support strategies for those most at risk.”

In the paper, the researchers called for sustained support for long Covid clinics and the development of treatment strategies that prioritise pain management, alongside other prevalent symptoms like neuropsychological issues and fatigue.

Given the significant impact of demographic factors on symptom severity, the study underscored the need for healthcare policies that addressed these disparities, ensuring equitable care for all individuals affected by long Covid, the researchers said.

Study limitations included a lack of information on other health conditions participants may have had and a lack of information about health history. The researchers cautioned that the study may have excluded individuals with very severe Covid and those facing technological or socioeconomic barriers in accessing a smartphone app.

The study was led by the UCL Institute of Health Informatics and the Department of Primary Care and Population Health at UCL in collaboration with the software developer, Living With Ltd.

A new study conducted by scientists at Northwestern University found that among PrEP users, many fear using PrEP puts them at risk of discrimination, even when they know other people who use the medication.

The study, published Aug. 16 in the journal Sexes, speculates about causes for self- stigma and recommends mitigation strategies to the Centers for Disease Control and Prevention, which aims to reduce new HIV infections in the United States by 90% by 2030.

“We are among the first to explore the perception of stigma attached to PrEP use among current PrEP users,” said quantitative researcher Shahin Davoudpour, the study’s first and corresponding author. “Typically, stigma-focused studies pay attention to stigmatizers rather than the stigmatized. Our findings are also novel as they show higher stigma perception among PrEP users — the group who we would expect to express the least stigmatizing behavior.”

Davoudpour is a research assistant professor of medical social sciences at Northwestern University Feinberg School of Medicine with a portfolio of research grounded in social stigma and HIV/AIDS.

Unlike stigma or discrimination on their own — which have been the topics of previous research — perceived stigma is a powerful social motivator, defined as the anticipation or fear of being discriminated against. By looking at the stigmatized rather than stigmatizers, the scientists hoped to gain better insight into why uptake of the medication has been slower than anticipated, as well as why PrEP users tend to be inconsistent in taking it.

Perceived stigma can be driven by several factors, often stemming from broader societal biases and misinformation about sexual practices and HIV risk. Davoudpour’s team examined two common measures of perceived stigma in PrEP use: the assumption that PrEP users are seen as promiscuous and the perception that people who use PrEP are HIV-positive.

The study used data from the baseline survey of an online study (which enrolled participants between 2017 and 2019) of a racially diverse population of over 3,000 sexual minority men, trans men and women, and non-binary individuals in the U.S. The “Keeping it LITE Study” collected data about PrEP use, persistence and attitudes, which the team ran through models to assess several stigma factors.

Davoudpour called the findings “significant and counter-intuitive,” including the conclusions that perception of stigma associated with PrEP remains high among PrEP users, and that that perceived stigma is not significantly reduced by knowing others who use PrEP.

“Current PrEP users are more likely to believe that PrEP users are promiscuous — a stigma marker — than those who have never used the medication,” Davoudpour said.

“PrEP was initially promoted for individuals most vulnerable to HIV — especially those with multiple sex partners and inconsistent condom use — thus its use has been inexorably tied to promiscuity,” said study co-author Gregory Phillips II, an associate professor of medical social sciences and preventative medicine at Feinberg. “However, PrEP can benefit a variety of people, including those in monogamous serodiscordant relationships (one partner is HIV-positive and the other is HIV-negative), but current messaging doesn’t reflect the broader array of potential PrEP users.”

Current marketing campaigns involving HIV preventatives tend to repeatedly highlight benefits of PrEP. Instead, the authors argue, “public health messaging can shift its focus to decreasing the perception of PrEP stigma among those vulnerable to HIV” via sex-positive messaging that disconnects PrEP from promiscuity and emphasizes its use among vulnerable populations.

This work was in part supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant numbers UH3AI133676 and UG3AI133676).

“This is the first comprehensive global analysis and we are very pleased with the data,” says Lamberto Manzoli, director of the School of Specialization in Hygiene and Preventive Medicine at the University of Bologna, who coordinated the study. “It was not a foregone conclusion: it took many years to develop a vaccine with such good results.”

The Dengue virus, transmitted by certain species of mosquitoes, infects about 400 million people annually in the warmer regions of the planet, causing more than 3 million deaths. Climate change is also expanding the habitat of the mosquitoes that carry the virus, leading to new Dengue outbreaks in an increasing number of countries. Even in Italy, with the continuous rise in cases, the disease is a major health concern.

Currently, there is no effective therapy against the disease, and environmental remediation actions against mosquitoes cannot eliminate the risk of epidemics. The only prevention strategy is therefore vaccination: approved in Europe in December 2022, the vaccine TAK-003, better known as Qdenga, has shown very promising results. However, until now, a comprehensive estimate of its effectiveness and safety was not available.

Researchers therefore examined and cross-referenced data from the 19 scientific studies conducted so far on the vaccine, to find solid evidence of its ability to combat the disease. Overall, the cases of over 20,000 individuals involved in the various tests were considered, even more than a year after the last administration, both with a single dose and with both doses required for complete vaccination.

The results show that the vaccine reduces the risk of contracting the disease by over 50%, with a high safety profile. Among those who received both doses, more than 90% developed antibodies against Dengue, and the response is very positive even among those who received only one dose: more than 70% of adults and more than 90% of children and adolescents develop antibodies.

“Given the results in terms of safety, immunogenicity, and efficacy, the administration of two doses can undoubtedly be a key tool for Dengue prevention,” confirms Maria Elena Flacco, director of the School of Specialization in Public Health at the University of Ferrara and the study’s lead author. “The currently available vaccine can therefore be very useful not only for populations in endemic areas but also for travellers from non-risk areas.”

The study was published in the journal Vaccines under the title “Immunogenicity, Safety and Efficacy of the Dengue Vaccine TAK-003: A Meta-Analysis.” The authors are Alessandro Bianconi, Matteo Fiore, and Lamberto Manzoli from the University of Bologna (Department of Medical and Surgical Sciences), along with Maria Elena Flacco, Giovanni Cioni, Giovanna Letizia Calò, Gianmarco Imperiali, Vittorio Orazi, Marco Tiseo, Anastasia Troia, and Annalisa Rosso from the University of Ferrara (Department of Environmental and Prevention Sciences).

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.”

In addition to OHSU, research institutions involved in the study included the Tulane National Primate Research Center, the University of Pittsburgh, the University of Washington, and the Washington National Primate Research Center at the UW.

In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to this research, OHSU and OHSU faculty involved in this research, including Jonah Sacha, Ph.D., have a significant financial interest in VIR Biotechnology Inc., a company that may have a commercial interest in the results of this research and technology.

All research involving animal subjects is reviewed and approved by a university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.

The research was supported by the Bill & Melinda Gates Foundation Grand Challenges grant awards OPP1213553 and National Institute of Allergy And Infectious Diseases of the National Institutes of Health award R01AI40888; with support from the Office of the Director of the National Institutes of Health award P51OD011092 to the Oregon National Primate Research Center at OHSU. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation or the National Institutes of Health.

IMAGE: JONAH SACHA, PH.D., SENIOR CO-AUTHOR OF A STUDY PUBLISHED TODAY IN THE JOURNAL NATURE COMMUNICATIONS, SAYS THE RESEARCH COULD LEAD TO A UNIVERSAL INFLUENZA VACCINE WITHIN FIVE YEARS.

view more CREDIT: OHSU/CHRISTINE TORRES HICKS

The paper, which publishes July 1^st in the journal BMC Global and Public Health, calls for greater investment in prevention of herpes transmission, including concerted efforts to develop effective vaccines against this common virus.

Corresponding author Nathorn Chaiyakunapruk, PharmD, PhD, professor of pharmacotherapy, and Haeseon Lee, PharmD, research fellow in pharmacotherapy, both at the College of Pharmacy of University of Utah Health, performed the research in collaboration with the World Health Organization and other academic institutions. They detail the associated economic cost estimates for genital herpes globally and by region.

Herpes is caused by infection with one of two types of the herpes simplex virus (HSV). Around two thirds of people (67%) aged 0-49 globally have HSV-1, according to the latest published statistics. It is mostly acquired in childhood, spreads by oral contact and causes infections in or around the mouth (oral herpes or cold sores). Adults can acquire genital HSV-1 infection through sexual contact if they were not infected during childhood. Type 2 spreads by sexual contact and causes genital herpes. Approximately 13% of the world’s population aged 15–49 years are living with HSV-2 infection.

In addition to sores and blisters, HSV can cause other more serious complications requiring healthcare attention, including a rare chance of mother to child transmission during childbirth, and increased risk of HIV infection.

More information on herpes: https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus

Let’s Talk Herpes video explainer: https://www.youtube.com/watch?v=U_r36QCnTPY

Based on data from the World Health Organization (WHO), the European Medicines Agency (EMA) selected the three most common strains of flu – a break from previous years in which four strains were targeted.

Influenza viruses continuously change and evolve. The periodic replacement of the virus strains contained in influenza vaccines is necessary to keep the vaccines effective. Every year, EMA issues recommendations for the composition of seasonal influenza vaccines based on trends seen last winter and monitoring data from the southern hemisphere flu season.

For 2024/2025, the Agency is recommending a transition from quadrivalent (four-strain) to trivalent (three-strain) vaccines that do not include the B/Yamagata component which was included last year. The B/Yamagata strain of the influenza B virus has not been detected in circulation since March 2020. This is thought to be due in part to the public health measures put in place to limit the spread of COVID-19 during the pandemic. Influenza B viruses are responsible for a quarter of annual influenza infections.

Manufacturers of live-attenuated vaccines, or egg-based trivalent vaccines should include these three virus strains for the 2024/2025 season:

• an A/Victoria/4897/2022 (H1N1)pdm09-like virus;
• an A/Thailand/8/2022 (H3N2)-like virus;
• a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

Manufacturers of cell-based trivalent vaccines should include these three virus strains for the 2024/2025 season:

• an A/Wisconsin/67/2022 (H1N1)pdm09-like virus;
• an A/Massachusetts/18/2022 (H3N2)-like virus;
• a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The EMA said manufacturers of inactivated vaccines can consider producing a quadrivalent vaccine containing two influenza B virus strains for the 2024/2025 season. ‘In that case a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus in addition to the strains mentioned above is considered appropriate,’ the Agency said in a statement.

Animal studies examined whether the treatment for preeclampsia could be applied to flu infections – and the results, according to the research team, were very promising.

Lead researcher and RMIT Post-Doctoral Research Fellow, Dr Stella Liong, said flu infections during pregnancy can resemble preeclampsia, a pregnancy complication that causes inflammation to the aorta and blood vessels.

Low-dose aspirin is commonly taken to prevent preeclampsia, as it stops the body from creating chemicals that cause inflammation.

“When the vascular system is inflamed, it leads to poor blood flow and affects the aorta’s function,” she said.

“This is especially a problem during pregnancy where good blood flow to the placenta is crucial to the development of the fetus.”

The research, led by RMIT University in collaboration with Trinity College Dublin, Ireland Professor John O’Leary and University of South Australia Professor Doug Brooks, found fetuses and placenta from mice with influenza A were smaller than those from uninfected mice.

Markers of low oxygen to the blood and poor blood vessel development were also evident in the fetuses.

However, mice treated daily with low-dose aspirin had less inflammation and improved fetal development and offspring survival.

While the research was still awaiting human clinical trials, Liong said low-dose aspirin was already recognised as safe to take during pregnancy.

However, the research team recommended pregnant people seek medical advice before taking new medications.

Brooks said influenza A infections during pregnancy was a big concern as every pregnancy overlaps with part of a flu season.

“There are long term implications for both the mother and the fetus, and aspirin might provide a simple solution for preventing this influenza associated pathology,” Brooks said.

Why flu infection is dangerous during pregnancy  

O’Leary said the research findings had huge implications for pregnancy and seasonal influenza virus infections for pregnant people.

“This study shines a light, for the first time, on the role of vascular inflammation associated with influenza virus and the potential dramatic effect of the disease-modifying drug aspirin, in low dosage, in pregnant women with co-morbid influenza,” O’Leary said.

While there weren’t many studies of the impacts of flu infections during pregnancy, project lead and RMIT Professor Stavros Selemidis said it was clear that pregnancy changed how the body responded to the virus.

Liong and Selemidis’ earlier breakthrough research found the flu virus during pregnancy could trigger a damaging hyperactive immune response, causing the virus to spread around the body from the lungs through the blood vessels.

“We used to think the flu virus just stayed in the lungs, but during pregnancy it escapes from the lungs to the rest of the body,” Selemidis said.

“This infection could set you up for cardiovascular disease later in life, but also set up cardiovascular disease in the offspring later in life.”

While vaccination was still the considered the best way to prevent flu infection during pregnancy, Selemidis pointed out vaccination rates were generally low in the pregnant population.

“Low vaccination rates aside, the flu shot may not generate the perfect immune response, especially if someone is pregnant or has an underlying medical condition,” he said.

“That’s why it’s useful to have a potential back up in low-dose aspirin to help prevent vascular dysfunction during pregnancy and improve fetal development.”

“Low dose aspirin prevents endothelial dysfunction in the aorta and foetal loss in pregnant mice infected with influenza A virus” was published in Frontiers in Immunology (DOI: 10.3389/fimmu.2024.1378610 ).

Madison Coward-Smith, Stella Liong, Osezua Oseghale, Jonathan R. Erlich, Mark A. Miles, Felicia Liong, Kurt Brassington, Steven Bozinovski, Ross Vlahos, Robert D. Brooks , Doug A. Brooks, John J. O’Leary and Stavros Selemidis are co-authors.

The test, developed by a team from the Broad Institute of MIT and Harvard and Princeton University, and supported by the US Centers for Disease Control and Prevention, uses CRISPR to distinguish between the two main types of seasonal flu, influenza A and B, as well as seasonal flu subtypes H1N1 and H3N2. It can also identify strains that resist antiviral treatment, and with further work, could potentially detect swine and avian flu strains, including H5N1, which is currently infecting cattle.

Appearing in The Journal of Molecular Diagnostics, the results could help improve outbreak response and clinical care by bringing tests that are accurate, low-cost, and fast to doctors’ offices and labs across the US and in other countries.

“Ultimately, we hope these tests will be as simple as rapid antigen tests, and they’ll still have the specificity and performance of a nucleic acid test that would normally be done in a laboratory setting,” said Cameron Myhrvold, co-senior author on the study along with Pardis Sabeti, an institute member at the Broad and a professor at Harvard University and the Harvard T.H. Chan School of Public Health, as well as a Howard Hughes Medical Institute investigator. Myhrvold, who is currently an assistant professor at Princeton University, was a postdoctoral researcher in Sabeti’s lab when the study began.

SHINE a light 

The test is based on a technology called SHINE, which was developed by Sabeti’s lab in 2020 and uses CRISPR enzymes to identify specific sequences of viral RNA in samples. The researchers first used SHINE to test for SARS-CoV-2, and later to distinguish between the Delta and Omicron variants. Then, in 2022, they began adapting the assay to detect other viruses they knew were always circulating: influenzas. They wanted to create tests that could be used in the field or in clinics rather than hospitals or diagnostic labs with expensive equipment.

“Using a paper strip readout instead of expensive fluorescence machinery is a big advancement, not only in terms of clinical care but also for epidemiological surveillance purposes,” said Ben Zhang, co-first author on the study, a medical student at Harvard Medical School and an undergraduate researcher in Sabeti’s lab when the study began.

Typical diagnostic approaches such as polymerase chain reaction (PCR) require lengthy processing times, trained personnel, specialized equipment, and freezers to store reagents at -80°C, whereas SHINE can be conducted at room temperature in about 90 minutes. Currently, the assay only requires an inexpensive heat block to warm the reaction, and the researchers are working to streamline the process with the goal of returning results in 15 minutes.

The researchers also adapted SHINE to distinguish between different flu strains. In the future, they say the assay could be adapted to detect two different viruses with similar symptoms, such as influenza and SARS-CoV-2.

“Being able to tease apart what strain or subtype of influenza is infecting a patient has repercussions both for treating them and public health interventions,” said Jon Arizti-Sanz, a postdoctoral researcher in Sabeti’s lab and co-first author on the study.

For example, the tests could help clinicians decide whether to use Oseltamivir, a common antiviral that is effective for only some strains, Arizti-Sanz added. In the field, rapid testing could also help scientists collect samples more strategically during an outbreak to better monitor how the virus is spreading.

Next, the researchers are adapting SHINE to test for both avian and swine influenza strains. “With SARS-CoV-2 and now flu, we’ve shown that we can easily adapt SHINE to detect new or evolving viruses,” Arizti-Sanz said. “We’re excited to apply it to H5N1.”

Paper cited
Zhang YB, Arizti-Sanz J, et al. CRISPR-based assays for point of need detection and subtyping of influenza. The Journal of Molecular Diagnostics. Online June 18, 2024. DOI: 10.1016/j.jmoldx.2024.04.004.

Children are generally more susceptible than adults to respiratory infections such as the common cold, and yet, for unknown reasons, the SARS-CoV-2 virus tends to cause less severe symptoms in children than in adults, resulting in lower rates of hospitalization and death during the COVID-19 pandemic. The innate immune system provides the first line of defense against viruses and bacteria, quickly producing a variety of anti-viral and proinflammatory proteins to fend off infection while the body develops other, more targeted, immune responses such as antibodies. Studies have shown that, compared with adults, the innate immune system is more active in the nasal passages of children and might therefore be better at blocking the early stages of SARS-CoV-2 infection. But the reason for this increased activity is unknown.

“Prior work suggested that heightened nasal innate immunity in children was due to intrinsic biological mechanisms inherent to their age,” says Ellen F. Foxman, associate professor of Laboratory Medicine and Immunobiology at Yale School of Medicine and the senior author of the new JEM study. “But we thought it could also be due to the high burden of respiratory viruses and bacterial infections in children.”

To investigate whether frequent respiratory infections are responsible for elevating nasal innate immunity in children, Foxman and colleagues re-analyzed more than 600 nasal swabs originally taken during the pandemic from pediatric patients about to undergo elective surgery or emergency room evaluation. Initially tested only for the presence of SARS-CoV-2, Foxman and colleagues re-screened the samples for 19 different respiratory viruses and bacteria, as well as measuring the levels of antiviral and inflammatory proteins produced by the innate immune system.

The researchers found that many children—even those without any symptoms—were infected with respiratory pathogens other than SARS-CoV-2. This was especially true for younger children, with viruses or infection-causing bacteria being detected in around 50% of asymptomatic patients under five years old. Children with higher levels of respiratory pathogens showed higher levels of nasal innate immune activity, regardless of whether they were toddlers or teenagers.

To further investigate the relationship between respiratory infections and nasal innate immunity, Foxman’s team compared nasal swabs taken from healthy one-year-olds at both a routine well-child checkup and a follow-up appointment one to two weeks later. Over half of the children tested positive for a respiratory virus on one of their two visits to the pediatrician, indicating that they had either acquired or cleared an infection in the intervening period. In almost every case, the child’s innate immune activity was higher at the time they were infected and lower at the time when they were virus free.

“This reveals that nasal antiviral defenses are not continually on high alert in young children but are activated in response to acquisition of a respiratory virus, even when that virus is not causing symptoms,” says Foxman.

Taken together, the study’s results indicate that the innate immune system is often highly activated in the nasal passages of children because they are frequently infected with relatively benign pathogens, such as the rhinoviruses responsible for the common cold. Foxman speculates that young children have more infections with common seasonal viruses than adults because they have less immunological protection from prior exposures (such as antibodies). However, since SARS-CoV-2 was a new virus to the human population, neither adults nor children had prior protection when the COVID-19 pandemic began. In this situation, activation of generalized antiviral defenses in children by other infections may have helped to fight off the initial stages of SARS-CoV-2 infection, leading to less severe outcomes in children compared with adults.

“We have identified respiratory viruses and bacteria as key drivers of the enhanced nasal innate immunity in children,” Foxman says. “Our results compel further study of how seasonal respiratory viruses and nasal bacteria impact disease severity of COVID-19 and pediatric immune responses in general.”

Watkins et al. 2024. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20230911?PR

IMAGE: THE NEW STUDY SUGGESTS THAT, BY FREQUENTLY ACTIVATING THE ANTIVIRAL AND PROINFLAMMATORY INNATE IMMUNE RESPONSE, COMMON RESPIRATORY VIRUS AND BACTERIAL INFECTIONS MAY HAVE HELPED TO PROTECT CHILDREN FROM SARS-COV-2.

view more CREDIT: ©2024 WATKINS ET AL. ORIGINALLY PUBLISHED IN <EM>JOURNAL OF EXPERIMENTAL MEDICINE</EM>. HTTPS://DOI.ORG/10.1084/JEM.20230911