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📆 22 December 2024 📰 Iconic Aussie species faces 'being lost forever' over $18 billion invasive threat

Cats transmit diseases such as toxoplasmosis, which costs the sheep industry $12 million annually through reduced lambing rates and other complications.

Toxoplasmosis is not only an agricultural issue but also a serious public health concern. The disease has been linked to miscarriages, mental health conditions, and neurological disorders. The estimated annual cost of cat-dependent diseases like toxoplasmosis to the Australian economy is approximately $6 billion.

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📆 20 Dec 2024 📰 Predicting flu evolution | Science Interviews 🗞️ Naked Scientists

Each year, influenza circulates globally, evolving and adapting as it goes, and its arrival in any given geography usually coincides seasonally with wintertime. This steady evolution changes the face that the virus presents to our immune systems and is what enables it to stay one step ahead of us and to keep coming back. For a vaccine strategy to work, scientists must try to anticipate sufficiently far ahead what forms of the virus will emerge in the forthcoming season, to give healthcare systems enough time to mass produce and administer an appropriate cocktail to protect the population. We get it right about 60% of the time. So why not 100%?

Richard - We know that influenza viruses adapt very rapidly to human immunity, meaning they mutate such that antibodies don't recognise the virus as well anymore as they used to. And these variants that have these immune escape mutations, these adaptive mutations, that tend to increase in frequency and our primary means of predicting future population would be that you look at the ones that grow in frequency, and extrapolate these frequency growths further into the future. But it turned out that many things that grow at some point stop growing and then just meander about this sort of curious growth is what triggered this work.

Chris - Is that because it grows and turns itself into a mutational disaster? Or is it because it grows flourishes but then we catch up, our immune response catches up and heads it off so then it it is kind of stuck

Richard - Yeah, we believe it is the latter. So, as these viruses grow in frequency and circulate, whoever gets infected by them generates immunity against them. So, in a way they are using up the susceptible populations that allows them to circulate and thereby their growth advantage ends up being diminished as their frequency increases.

Chris - Why do they not though just stay one step ahead of us continuously and just keep on changing? So, that they can continue to grow and we are always playing catch up

Richard - To some extent they do, but sometimes you have a mutation that endows a virus with a particular advantage, but from there it's stuck in a place where it can't really go further. But some other viral lineages that also circulate, they tend to have gone a different path than mutational space that offers them more future opportunities to further adapt. So, there is sort of a way in which viruses can back themselves into a corner and while they have a transient advantage, then they're sort of stuck in a place while other ones that were initially not as successful then overtakes them.

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📆 19 Nov 2024 📰 Can COVID-19 Provide a Breakthrough in Cancer Therapy? Scientists Explore Potential Benefits

"This discovery opens up a new avenue for cancer treatment," said Dr. Ankit Bharat, senior author and chief of thoracic surgery at the Canning Thoracic Institute. "We found that the same cells activated by severe COVID-19 could be induced with a drug to fight cancer, and we specifically saw a response with melanoma, lung, breast, and colon cancer."

The study focuses on "inducible nonclassical monocytes" (I-NCMs), a rare type of immune cell that multiplies in response to inflammation, such as that seen during severe COVID-19 infections. Unlike typical immune cells, which patrol blood vessels for threats but often cannot penetrate tumors, I-NCMs retain a unique receptor, allowing them to infiltrate tumor tumor sites and trigger an aggressive immune response.

"Once inside the tumor environment, these cells release chemicals that recruit the body's natural killer cells," Bharat explained. "These killer cells swarm the tumor and start attacking cancer cells directly, helping to shrink the tumor."

In preliminary tests, a compound that mimics the effect of COVID-19 RNA reduced tumors by up to 70% in mice with human cancers. Researchers believe this approach could be particularly beneficial for patients with stage 4 cancers who have exhausted other treatment options.

The study builds on related observations, including a case documented in the British Journal of Haematology. In that instance, a man diagnosed with terminal stage III lymphoma experienced significant tumor regression after contracting COVID-19. Within months of recovering from the respiratory illness, his tumors disappeared, highlighting the potential link between immune system activation during infection and cancer response.

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📆 12 Jan 2024 📰 Dengue fever cases in Switzerland on the rise post Covid 🗞️ Le News

Over the last two years the number of dengue fever cases registered in Switzerland has increased tenfold to 261, reported SRF. In 2021 only 26 cases were recorded across Switzerland.

Claudio Zaugg at the Federal Office of Public Health (FOPH) said that the strong increase reflects low numbers during the Covid-19 pandemic. Swiss dengue cases are imported and follow the amount of foreign travel. With the resumption of travel after the pandemic cases of dengue have risen dramatically. However, even without the effects of a sharp drop in travel during Covid the number is rising.

Dengue fever is transmitted by mosquitoes, especially in Latin America, Southeast and South Asia and parts of Africa. The number of cases is on the rise worldwide. 10 years ago the number of cases worldwide was a tenth of what it is today. Experts expect this trend to continue.

Some disease experts eventually expect to see the emergence of home grown cases of dengue fever in Switzerland. The tiger mosquito, which is becoming more common in Europe, is an ideal vector for the disease.

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📆 21 November 2023 📰 Polio is on the brink of eradication. Here's how to keep it from coming back

Industrialized, polio-free countries use an inactivated poliovirus vaccine (IPV), which doesn’t prevent the virus infecting the body and being shed in stools, but does protect against paralysis. Provided that immunization levels with IPV remain high and sanitation is good, a rogue poliovirus will probably peter out, according to Concepcion Estivariz, a polio researcher at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

But because the inactivated vaccine can’t block transmission, children in at-risk countries still receive another type: an oral poliovirus vaccine (OPV) that contains an attenuated form of the live virus, and can stop polio’s spread — which is crucial for eradication. It’s also cheaper and easier to deliver than IPV, which is administered by injection. The oral campaign has been hugely successful. Since 1988, the Global Polio Eradication Initiative (GPEI) estimates it has prevented 20 million cases of polio paralysis.

But OPV has some important downsides. There is a low risk that the vaccine itself can cause paralysis. And, on rare occasions, the weakened virus used in the vaccine can mutate sufficiently to regain virulence. This can lead to outbreaks of cases known as vaccine-derived polio among people who have not been vaccinated fully or at all. “If we continue OPV,” says Estivariz, “we never stop the circle.” Most countries are now using IPV in their routine immunization programmes alongside OPV, and the WHO recommends that IPV administration should continue for a decade after disease transmission has been stopped, to protect against any accidental releases or hidden pockets of the virus.

Polio will be certified as eradicated when no case has been observed for three years, and when there is no sign of it in environmental surveillance data — that is, in samples of waste water. A year after that, OPV must be withdrawn to prevent vaccine-derived polio. The problem, however, is that removing it will be an extraordinarily delicate manoeuvre. Done messily, this process could trigger the return of the virus.

In 2016, for instance, the withdrawal of an OPV across 150 countries went disastrously wrong. “The results were sobering”, says Kimberly Thompson, an epidemiologist at the research non-profit organization Kid Risk, in Orlando, Florida.

There are three strains of wild polio — types 1, 2 and 3. Type 2 was declared eradicated in 2015, and type 3 followed in 2019. The oral vaccine contained attenuated versions of all three strains, but after type 2 was eradicated, the aim was to withdraw vaccines containing that strain to minimize the risk of seeding vaccine-derived type 2 polio. So the GPEI orchestrated a two-week period in April 2016 in which all three-strain oral vaccines were switched for versions containing just types 1 and 3.

Swiftly, however, cases of vaccine-derived type 2 polio began to build — in two countries in 2016, spreading to 24 countries by 2020, with countries in Africa worst affected. A case popped up in the United States in 2022, and the United Kingdom found the virus in wastewater samples. The cumulative number of paralysis cases so far is just over 3,200; the yearly total peaked at more than 1,000 in 2020 and now seems to be declining, with 238 recorded so far this year (see ‘Rare and receding: vaccine-derived polio’). African countries are still running multiple emergency campaigns delivering oral type 2 vaccines to stamp these outbreaks out.

Why the rebound? First, populations in the regions affected weren’t sufficiently vaccinated beforehand with IPV, which would have protected them until any outbreaks could be controlled. This was partly owing to a gap in vaccine supply, says Ondrej Mach, who co-chairs a new GPEI group that will oversee future withdrawals of the oral vaccine.

Since 2021, however, this seeding has become much less likely: vaccination campaigns are controlling the outbreaks using a genetically engineered oral vaccine, which has an even lower chance of becoming virulent than the OPVs used previously.

A surprising source

There is yet another source of poliovirus, unforeseen 35 years ago when eradication efforts began. In most people who receive the oral vaccine, the immune system generates antibodies that protect them against the virus. But in a small number of people born with particular immune deficiency disorders, the immune system allows the attenuated virus from the vaccine to live on, evolving as time goes by and emerging in their stools. No drugs have been proved to cure an ongoing polio infection.

Only some of the several hundred types of immunodeficiency lead to chronic retention of poliovirus. No one knows how many people are affected, and no such shedding is known to have triggered a polio outbreak, although it might have contributed to one in the Philippines in 2019–21.

But, says Mach, even one person retaining and shedding poliovirus is incompatible with eradication. “We have to do something.” An international — if patchy — search for people with these immune disorders who have chronic polio has produced a register of 200 individuals.

One person with the condition lives in the United Kingdom and was vaccinated with OPV as a child. For more than 20 years, he asymptomatically carried — and shed — the attenuated virus, which evolved to its disease-causing form. His gut was “essentially a culture vessel”, says David Boyle at PATH, a non-profit medical-research organization based in Seattle, Washington.

That’s why scientists were surprised to learn that the person’s infection had gone.

It disappeared after he received the antiviral drug remdesivir for severe COVID-19 in August 2021. This could be coincidence, says Macadam, but it bolsters the case that antivirals could be used to treat polio infection (two such drugs are being explored as polio treatments). Monoclonal antibodies are also under development.

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📆 Nov 2020 📰 Pros and Cons of Adenovirus-Based SARS-CoV-2 Vaccines 🗞 PubMed Central

Most of us might be surprised by the rudimentary scientific rationale prevalent in the field of vaccine research just 50 years ago. For over a century after Louis Pasteur’s vaccine against rabies, approaches usually consisted of inactivating a virus, injecting it, and seeing if it protected the host. Unlike today, interactions between vaccinologists and immunologists to improve vaccine efficacy were marginal.

With the rise of molecular biology, vaccine designs became more nuanced and the use of viral vectors emerged. An example is the evolution and checkered history of vaccines based on adenoviruses (Ads). Live Ad types 4 (Ad4) and 7 (Ad7) have been used in North American military recruits since the 1950s to prevent severe respiratory illness.1 Similarly, dogs in western countries are vaccinated with an attenuated canine Ad type 2 (CAV-2) to prevent infection of the more virulent CAV-1...

... After almost 70 years of working with Ads, their biochemical properties are well characterized: Ads are simple to make (in ∼2 weeks a graduate student could generate enough of a novel Ad vaccine to treat a thousand mice and dozens of monkeys), easy to purify to high titer, genetically stable, easily stockpiled, relatively inexpensive, and can be delivered via aerosol, oral, intradermal, and intramuscular routes...

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📆 03 Jan 2020 📰 Identification of antigens presented by MHC for vaccines against tuberculosis 🗞 npj Vaccines

Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry.

We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated with membranes and involved in lipid biosynthesis and transport.

The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease.

Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens.

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📆 May 1996 📰 Immunologic properties of Epstein-Barr virus-seronegative adults

Epstein-Barr virus (EBV) seronegativity is rare in people > 20 years old. However, some persons remain EBV-seronegative for nearly their whole lives. The aim of this study was to examine properties of the immune system of EBV-seronegative adults that could contribute to long-term EBV seronegativity. Therefore, differential blood cell counts and lymphocyte subpopulations were determined, and the production of interferon (INF)-alpha and -gamma and interleukin (IL)-6 and -2 in a whole blood assay was investigated. Whereas no differences in the distribution of lymphocyte subpopulations between EBV-seronegative and -positive adults were found, a significant higher percentage of monocytes in EBV-seronegative adults was observed.

Significantly more IFN-alpha and IL-6 were detected in culture supernatants of EBV-seronegative persons after stimulation with Newcastle disease virus. In contrast, no differences in the induction of the lymphokines IFN-gamma and IL-2 were seen. These data suggest that faster and higher production of IFN-alpha and IL-6 amy protect EBV-seronegative adults against EBV infection.

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📆 23 Nov 2023 📰 The Relationship Between Epstein-Barr Virus and Multiple Sclerosis ✍️ Bridget A. Bagert 🗞 Neurology Live

In January 2022, Bjornevik and colleagues published the results of a 20-year prospective seroepidemiologic study on the relationship between Epstein-Barr virus (EBV) and multiple sclerosis (MS) in which investigators observed an enormous increase in the risk of MS after EBV infection. They concluded that EBV is the leading cause of MS.

In fact, the idea of an association between EBV and MS is not at all new. The relationship has been suspected for more than 40 years, and evidence therein has been accumulating over the past 2 decades in various fields of medical science, including pathology, epidemiology, immunology, and clinical trials.

In 1980, Sumaya and colleagues were among the first of several groups to report a differential EBV antibody response in patients with MS compared with controls.2 In 2001, Ascherio and colleagues reported on the first prospective seroepidemiologic study addressing this question; the results identified a significantly increased risk of MS after EBV infection.3 Similar prospective seroepidemiologic studies were then conducted in both the United States and Europe in the ensuing decade. In 2013, Pakpoor and colleagues published a meta-analysis of this body of prospective seroepidemiology and concluded that, for an EBV seronegative individual, the odds of developing MS are null.

In 2008, Hauser and colleagues reported the robust and surprising effectiveness of the anti-CD20 drug rituximab (Rituxan; Genentech/Biogen) in a phase 2 trial in relapsing-remitting MS.16 This observation ultimately led to the development and 2017 approval of ocrelizumab (Ocrevus; Genentech), a humanized anti-CD20 agent that has proven to be among the most highly effective disease-modifying therapies for MS available.

The fact that 90% to 95% of the general population have EBV antibodies, yet only a small fraction of them develop MS, adds to the complexity of this story...

... It is established that mononucleosis, a late primary EBV infection that occurs in adolescence, is associated with a higher risk of MS.19-21 Primary EBV infection in infants, by contrast, is usually asymptomatic.22 It is interesting to speculate how a late primary EBV infection may lead to the cascade of immunological events that result in MS. The immune response of adolescents to primary EBV infection is fundamentally different from that of infants. Specifically, in cases of mononucleosis in adolescents, there is a massive expansion of CD8+ T cells in that is not seen in infant infections...

It is also interesting to consider differences in modern hygiene practices that may account for observed differences in the prevalence of primary EBV infection, and whether these changes may influence MS risk. EBV infection is more prevalent in infants than in adolescents in communities with lower socioeconomic status and poor hygiene standards,24,25 and it is well established that the prevalence of MS is lower in countries with lower socioeconomic status than in developed countries. In other words, in countries where primary EBV infection typically occurs in infancy, MS prevalence is lower, and in countries where primary EBV infection commonly occurs in adolescence, MS prevalence is higher, suggesting that the timing of EBV infection may be an important factor in MS risk. Considering that humans have coevolved with EBV over millions of years,26 perhaps the human immune system has evolved in turn to manage EBV more successfully in infancy than in adolescence.

Speculating further on the relationship between the timing of EBV infection and MS risk, the mode of viral transmission may be another key. EBV is transmitted via oral secretions. Throughout human history infants would have been exposed to EBV reliably through the premastication of food passed from mother to child.27-31 The practice of premastication has all but disappeared in modern developed societies, and perhaps with it the opportunity to inoculate young children with EBV at the time in their lives when their immune systems are best able to manage it. Could these relatively recent changes in human hygiene practices explain, in part, the modern increase in the incidence of MS?

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In influenza virus infection, cytotoxic T-cells target conserved non-structural proteins while antibodies target the divergent neuraminidase and hemagglutinin proteins and are thus strain-specific. In 1983, McMichael and colleagues demonstrated that individuals with cross-reactive T-cells targeting influenza A were able to clear infection in the absence of subtype-specific antibody (55). Later studies showed cross-reactive CD4+ and CD8+ T-cells are associated with milder disease in individuals lacking cross-reactive antibody (56, 57).

Animal challenge models have shed light on whether cellular immunity following vaccination can confer protection against influenza. Vaccination of mice with a virus-like particle vaccine against influenza A virus promoted cross-reactive CD8+ T-cell-mediated protection against later challenge with a heterosubtypic strain, supporting the idea that cellular immunity in the absence of subtype-specific antibody can confer protection against infection.

📆 Jan 2023 📰 Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion 🗞 Frontiers

Determining which antigens are targeted in SARS-CoV-2 ESNs provides insight into mechanisms of response. T-cells targeting the replication-transcription complex (RTC) of SARS-CoV-2 were described by Swadling et al. (2022) in ESNs (7). The RTC is comprised of the RNA polymerase NSP12, a co-factor NSP7, and the helicase NSP13 (37). Its expression early in the SARS-CoV-2 replication cycle makes the RTC a target for rapidly-induced T-cell responses (7). The authors identified fivefold-higher RTC-specific T-cell responses in ESNs compared to unexposed controls. Furthermore, cellular immunity in ESNs preferentially targeted the RTC over structural proteins compared to seropositive individuals. However, the authors did not assay cellular responses to other NSPs.

In a study of six ESN sexual partners of HSV-2-infected individuals by Posavad et al. (2010), T cell responses in ESNs were skewed towards peptides expressed early in the virus replication cycle, whereas HSV-2 seropositive individuals more frequently generated responses to structural proteins present in virions. The authors speculated that this skew in ESNs reflected early T-cell engagement with infected cells before the production of infectious virions. Together, these data support a model whereby rapid T-cell responses targeting early translated NSPs may prevent infection from gaining a foothold.

To prevent infection before seroconversion, a rapid cellular response appears critical. Chandran et al. (2021) assayed weekly nasopharyngeal swabs and blood samples from HCWs, and demonstrated that SARS-CoV-2 specific T-cell proliferation can occur before PCR positivity (42). These rapid responses may originate from pre-existing, cross-reactive T-cells specific for human coronaviruses (HCoVs). Cross-recognition of SARS-CoV-2 by HCoV-specific T-cells has been widely described (43–50), and T-cells from COVID-19 convalescents preferentially target conserved epitopes over SARS-CoV-2-specific epitopes (49). HCWs display higher levels of HCoV-specific T-cells than community controls (28), which may contribute to the abundance of ESNs amongst HCWs. The activation of cross-reactive T-cells by related viruses has been termed ‘heterologous immunity’ (51). This is distinct from autologous viral infection in that neutralising antibody responses to the heterologous virus may be suboptimal, allowing cellular memory to dominate.

The RTC is highly conserved between SARS-CoV-2 and HCoVs (7). Tetramer staining of T-cells with an HCoV-HKU1 homologue of the RTC component NSP7 showed strong responses in SARS-CoV-2 ESNs. Swadling et al. (2022) suggested that prior exposure to HCoV-HKU1 generates cross-reactive T-cells specific for NSP7, enabling rapid abortion of SARS-CoV-2 infection (7). A study of camel workers in Saudi Arabia identified both CD4+ and CD8+ responses to Middle-East Respiratory Syndrome coronavirus in four highly-exposed seronegative individuals, suggesting that the ESN phenomenon may be common to other human-infective coronaviruses.

Cellular immunity is able to clear SARS-CoV-2 infection in isolation; patients with X-linked agammaglobulinemia who cannot produce antibodies eventually clear SARS-CoV-2 infection, and mount higher magnitude CD8+ T-cell responses to SARS-CoV-2 compared to immunocompetent individuals (54). However, in Wang et al. (2021) the magnitude of the SARS-CoV-2-specific CD4+ T-cell response was twice as high in infected individuals compared to ESNs. This casts doubt on their role in protection against infection.

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📆 Nov 2021 📰 Why is the flu shot less effective than other vaccines? ✍️ Nicoletta Lanese 🗞 Live Science

The seasonal flu shot typically trains the body to fight four types of influenza virus, according to the Centers for Disease Control and Prevention (CDC): two influenza A viruses of the subtypes H1N1 and H3N2, and two influenza B viruses from the so-called Victoria and Yamagata lineages, which refer to branches of the influenza family tree. These influenza viruses mutate rapidly from year to year, meaning their genetic code changes and the proteins that appear on their outer surfaces change rapidly, too.

The flu shot works by training the immune system to recognize one of these surface proteins, called hemagglutinin (HA), which juts off the virus "like a lollipop on a stick," said Dr. William Schaffner, an infectious disease specialist at Vanderbilt University in Tennessee. Similar to the novel coronavirus's infamous spike protein, the HA protein enables influenza viruses to bind to and infiltrate cells to infect them. And the HA protein mutates rapidly, essentially doing a costume change every year and thus making it hard for the immune system to recognize it.

Another challenge is that flu shots must be manufactured and ready to go before flu season, so scientists use various strategies to predict which flu strains will be circulating in the coming months.

"You try to anticipate which strains are going to be active during your winter, early," Schaffner said. "But we have to project, because it takes time to make the vaccine." And even as the vaccine is being prepped, the circulating viruses can keep on mutating, sometimes to the point that they no longer match the shots well. And by the time flu season begins, the influenza strains scientists thought would be most prevalent can sometimes be overtaken by other versions of the viruses.

To predict which flu strains will dominate in the upcoming season, more than 140 national influenza centers in 113 countries collect swab samples from people who get flu-like sicknesses throughout the year, identifying those who actually caught influenza, according to Scientific American. Five World Health Organization-affiliated centers then do gene sequencing of the samples, characterize the proteins that lie on the viral surface, and run laboratory tests to see how well past vaccines neutralize the circulating flu strains, according to the CDC. They also determine which strains appear to be making the most people sick, and how fast the strains are spreading.

To predict which flu strains will dominate in the upcoming season, more than 140 national influenza centers in 113 countries collect swab samples from people who get flu-like sicknesses throughout the year, identifying those who actually caught influenza, according to Scientific American. Five World Health Organization-affiliated centers then do gene sequencing of the samples, characterize the proteins that lie on the viral surface, and run laboratory tests to see how well past vaccines neutralize the circulating flu strains, according to the CDC. They also determine which strains appear to be making the most people sick, and how fast the strains are spreading.

"Sometimes, the choice is right on target," Schaffner said. And then "there are other times that the flu manages to evade our predictions."

That said, even when there's a "good match" between the vaccine strains and circulating strains, the shots only tend to be about 40% to 60% effective. This modest effectiveness may be related to the fact that the shots target only the HA protein, rather than multiple spots on the influenza virus, and that the human immune system can sometimes be undermined by its previous exposures to the flu, Science magazine reported.

The natural immune response to an influenza infection involves generating antibodies against multiple proteins on the viral surface, not just HA, according to a 2013 report in Clinical Microbiology Reviews. The vaccines, by comparison, primarily generate antibodies against the HA protein, and it's unclear if targeting additional surface proteins could boost the shots' effectiveness, Science magazine reported.

Our first exposures to the flu in childhood may also bias how the immune system responds to vaccination, sometimes to our detriment, according to Science. After its first flu exposure, the body generates long-lived memory B cells, immune cells that remember the virus and can reactivate to produce more antibodies in the future. Some evidence suggests that later, if one is vaccinated against a similar — but not identical — flu virus to the first one they encountered, the body may reactivate these memory B cells, which crank out antibodies that miss their intended target.

Many flu vaccines are tested in ferrets that have never been exposed to flu before, so it's difficult to know whether the shot will work similarly in humans who've likely encountered flu viruses several times before.

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📆 Nov 2004 📰 Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

Hepatitis C virus (HCV) is a frequent cause of liver disease, leading to chronic infection in as many as 170 million persons worldwide. Vaccine development for HCV, like that for human immunodeficiency virus type 1 (HIV-1), is limited by the quasispecies nature of the virus as well as a lack of clear evidence that humoral immune responses protect against infection. Unlike patients with HIV-1, some individuals infected with acute hepatitis C can recover, although the asymptomatic nature of acute infection in most infected persons and the relative difficulty in conducting prospective studies have limited our understanding of the correlates of recovery from infection....

... However, the small numbers of individuals who can be identified as having spontaneous recovery and the retrospective nature of such studies may underestimate the true rates of clearance.

... Similar findings have been noted in persons repetitively exposed to HIV-1 without seroconversion. HIV-specific CD4+ T-helper cells and CTL have been detected in persons exposed through sexual contact (18, 25) or contact with contaminated blood (3, 23) as well as in seronegative infants of infected women (5, 26). These studies have shown recognition of diverse epitopes in these highly exposed but seronegative individuals, although the repertoire of epitopes recognized by HIV-infected and uninfected persons may be different (21, 24).

... Given the limited number of patients with acute HCV viremia who go on to resolve infection, determining the epitopes recognized by individuals who remain uninfected despite repetitive exposure may be another method of defining the nature of the protective immune response. One implication of these findings is that definition of infection solely on the basis of the presence of antibody at a single point in time may significantly underestimate the true rate of infection, and future prospective studies assessing factors associated with risk of infection or clearance may have to include measurement of cellular immune responses. It has been shown that some individuals at high risk for HCV, such as intravenous drug users, remain seronegative despite ongoing risk. Measurement of cellular immune responses in these populations might provide additional insight into the nature of protective immunity in HCV and further aid in vaccine development.

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📆 May 2020 📰 A Look at Each Vaccine: Polio Vaccine

Polio vaccine has been available since 1955. The inactivated polio vaccine (IPV) was available first, given as a shot, in 1955. A more convenient form, called oral polio vaccine (OPV), was given as liquid drops via the mouth. It was developed in 1961. OPV was recommended for use in the United States for almost 40 years, from 1963 until 2000.

OPV was made by weakening the three strains of poliovirus that caused disease by growing them in monkey kidney cells. Poliovirus that was grown in these cells was so "weakened" that, after it was swallowed, it induced an immune response but didn't cause disease.

OPV induced antibodies in the intestines and, therefore, because polio enters the body through the intestines, provided a "first line" of defense against polio. Unfortunately, on occasion, OPV reverted back to the natural form, causing paralysis.

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📆 Mar 2004 📰 The M1 matrix protein controls the filamentous phenotype of influenza A virus

Below the host-derived lipid bilayer that forms the envelope of the influenza A virus particle lies a layer of matrix protein, M1. This is the most abundant protein of the virion, and it possesses both nucleic acid and membrane binding activity Bucher et al., 1980, Wakefield and Brownlee, 1989.

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📆 18 Jan 2023 📰 How your first brush with COVID warps your immunity ✍️ Rachel Brazil 🗞️ Nature

Imprinting was first observed in 1947 by Jonas Salk and Thomas Francis, the developers of the first flu vaccine, together with another scientist, Joseph Quilligan1. They found that people who had previously had flu, and were then vaccinated against the current circulating strain, produced antibodies against the first strain they had encountered. Francis gave the phenomenon the tongue-in-cheek name ‘original antigenic sin’, although today most researchers prefer to call it imprinting.

📆 03 May 2023 ✍️ ALICE PARK 📰 Why It Took So Long to Finally Get an RSV Vaccine 🗞️ Time

On May 3, the U.S. Food and Drug Administration (FDA) approved the first vaccine against RSV, from GlaxoSmithKline (GSK), to prevent respiratory disease in people ages 60 and older.

In the 1980s, Paul Glezen, a microbiologist and immunologist at Baylor College of Medicine, made the first important discovery toward creating an RSV vaccine. Doctors knew that while nearly every baby became infected with RSV by the time they were two, only a small percentage became sick enough from their infection to be hospitalized. He guessed that most babies were benefiting from antibodies that they passively received from their mothers, which helped their still undeveloped immune systems fight off the virus. To prove his theory, Glezen collected cord blood from thousands of babies born at Baylor’s maternity hospital, and compared those who ended up being hospitalized for RSV to those who were not. The babies who did not get admitted tended to have high levels of antibodies against the virus, while those who did not had lower levels.

“That was a fundamental breakthrough,” says Bill Gruber, senior vice president of vaccine clinical research and development at Pfizer. “It indicated that if you could get the right antibodies to the babies, they would likely provide protection against RSV.”

That insight turned into an antibody treatment: an injectable shot known as palivizumab, or Synagis. This is currently the only antibody-based therapy for RSV, but it’s reserved for babies at highest risk of developing infections and requires five shots over the course of one viral season.

A vaccine that trains the immune system to fight the virus would have broader impact and could be more widely distributed to every newborn as part of their routine immunizations. But after an early vaccine candidate failed to protect babies and instead led to worse illness—particularly among those who had never been exposed to the virus before getting immunized—development stalled for decades. “That vaccine, which was given to infants, made things worse and set back research years and years,” says Dr. Phil Dormitzer, global head of vaccines R&D at GSK.

Scientists working on another virus, parainfluenza virus, that also causes respiratory disease in babies, first introduced the idea that an effective vaccine against that pathogen should target a specific form that the virus takes, just before it infects a cell. Previous attempts to develop vaccines had targeted the wrong form of the RSV protein—one that the virus made after it had infected cells. By then, the virus had already co-opted the cell’s machinery to make more copies of itself, and had launched a full scale infection—too late for any vaccine to come in and have much effect. Once the idea had been planted with the parainfluenza virus, “we assumed that we could do the same thing with RSV, and that it would be pretty easy to engineer,” says Dormitzer. “But it turned out to be way more difficult, and many frustrating years went by when we tried to do the same thing with RSV, with minor variations, and they weren’t working.”

Then, Barney Graham made a breakthrough discovery in 2013. An immunologist and virologist at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Graham had devoted years to unpacking how RSV worked. He focused on understanding how the main RSV protein that sets up a red flag for the immune system was constructed. Graham successfully isolated a version of the protein that the virus made before infecting a cell, and in tests in animals and with human cells, this protein was far more potent in stimulating the immune system than previously isolated RSV proteins.

At Pfizer, Gruber, who was Graham’s undergraduate roommate at Rice University, learned of his friend’s discovery after reading Graham’s description in a scientific journal. The two connected, and Gruber convinced Pfizer to license the technology. The pharmaceutical giant put its scientists to work creating a stabilized form of the RSV protein that targeted not just one strain of the virus, but two—similar to the way different versions of the influenza virus are included in each flu shot—in order to prompt the most wide ranging immune response possible.

GSK relied on its own strategies using recombinant technology to ensure that the target RSV protein did not “flip to a form we didn’t want,” says Dormitzer. The engineering in GSK’s vaccine, he says, has advantages in that scientists can perform quality control to ensure that the RSV protein in the shot is pure and in the proper form, and gives them more control over how the vaccine can activate the immune system.

Graham was preparing to launch a trial of his RSV protein in a vaccine toward the end of 2019. But it turned out the first virus his theory would be tested against wouldn’t be RSV, but SARS-CoV-2. Based on his work with RSV to that point, Graham was among the first to realize that the same approach he was testing for a new RSV vaccine could work for the novel coronavirus as well. He asked his boss, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, to allow him to test that idea and develop a prototype COVID-19 vaccine with a form of SARS-CoV-2.

[thebrokencrescent-blog]

📆 Mar 2023 📰 Rapid Mutation Helps RSV Evade Vaccines: Study

A recent study published in the journal Virus Evolution found that RSV is capable of evading vaccines because of its ability to rapidly mutate.

The research team decided to focus on the evolutionary dynamics of the virus to understand its spread and genomic variability. The researchers collected nasopharyngeal samples from hospitalized pediatric patients in Buenos Aires, Argentina, who tested positive for RSV from 2014 to 2017.

Several vaccine candidates are in the final stages of clinical testing, with the advisory panel of the U.S. Food and Drug Administration (FDA) already recommending the use of two candidates from Pfizer and GSK in older adults. But for Suman Das, Ph.D., an associate professor of Medicine in the Division of Infectious Diseases at Vanderbilt University Medical Center, vaccination may not readily solve the problem caused by RSV.

"Once the vaccine comes, this is the beginning and not the end. If we have the vaccine, the virus will evolve faster. The same thing happened with COVID-19. We need to understand what kind of mutation is happening, and whether (it) will affect the efficacy of the vaccines,” Das, who worked on the recent study, said in a press release.

For Das and his colleagues, surveillance and sequencing programs should be carried out to ensure that the vaccines being developed could counter the current strains. Should the ones that will be approved later this year fail to cover the newer strains, they can be updated.

“We need to know where the virus is evolving, and how vaccines are driving evolution. We want to be ahead of the game,” Das said.

[thebrokencrescent-blog]

📆 Oct 2019 📰 Protective Immunity and New Vaccines for Lyme Disease 🗞 PubMed Central

Live-attenuated mutant vaccines have been proven to be effective for immunization against several contagious infectious diseases. In terms of B. burgdorferi infection, live-attenuated flagella-less and p66 mutants of B. burgdorferi can elicit partial or fully protective immunity in mice [22]; these mutants are also more effective than killed bacteria.

Although such live mutants are incapable of establishing infection in mammalian hosts, this approach is unlikely to be used for human applications. Nevertheless, it could lead to identification of some individual targets with protective efficacy to develop new recombinant vaccine candidates; further, these mutants could be used to develop additional reservoir-targeted or other animal vaccines.

📆 Mar 2020 📰 Defining trained immunity and its role in health and disease 🗞 Nature Reviews

For a long time it was assumed that immunological memory was an exclusive hallmark of the adaptive immune response. However, a growing body of literature indicating that innate immune cells — and even tissue-resident stem cells — can show adaptive characteristics has challenged this dogma4,5,6,7,8. Greater protection against reinfection — a de facto immune memory function — has also been reported in plants and invertebrates9,10,11, which lack an adaptive immune system. This demonstrates that adaptation of host defence can occur on the basis of innate-like immune mechanisms. Moreover, certain infections and vaccinations can induce broad protection against other pathogens through innate immune mechanisms...

Many studies in mice have documented the existence of adaptive characteristics of innate immunity. Together, these studies demonstrated that training mice with different microbial ligands could protect against subsequent lethal infection in a non-specific manner. For example, treatment with the fungal ligand β-glucan protected against subsequent infection with Staphylococcus aureus24,25, while the peptidoglycan component muramyl dipeptide induced protection against Streptococcus pneumoniae and Toxoplasma gondii infections...

An increasing body of evidence suggests that trained immunity plays a critical role in humans. First, an extensive collection of epidemiological data argues that live vaccines such as the BCG vaccine, measles vaccine, smallpox vaccine and oral polio vaccine have beneficial, non-specific protective effects against infections other than the target diseases40,41,42,43,44,45,46,47 (for a review, see also ref.48). Subsequently, proof-of-principle trials with the BCG vaccine in adults23,49 and children50,51 demonstrated that this vaccine induces non-specific activation of innate immune cells.

Interestingly, both epidemiological and immunological studies have shown that the vaccine effects may last for months, but may also be modified or even reversed when a non-live vaccine is given52,53. Furthermore, BCG vaccination led to protection against microorganisms in models of controlled human infection, such as yellow fever54 or malaria55, and this was associated with an augmented proinflammatory activity of monocytes (Box 1). Second, certain infections, such as malaria, induce a state of hyper-responsiveness that is functionally equivalent to induction of trained immunity56,57,58.

Finally, there is evidence that BCG vaccination can induce antitumour immune effects leading to the prevention or treatment of malignancies such as bladder cancer59, melanoma60, leukaemia61 and lymphoma62. Notably, these anticancer effects of BCG seem to be dependent on its capacity to induce trained immunity in monocytes and macrophages63.

Trained immunity was initially shown to act through mature myeloid cells. Until recently this hypothesis resulted in a conundrum as mature myeloid cells, such as monocytes and DCs, in both mice and humans are short-lived, with an average half-life of 5–7 days100,101,102. Therefore, how trained immunity can be maintained in myeloid cells for several months, years and even decades41 remained unknown. More recent work has helped to resolve this issue by showing that trained immunity can occur in bone marrow progenitor cells (central trained immunity), as well as in blood monocytes and tissue macrophages (peripheral trained immunity) (Fig. 2).

In the past decade, a unique anamnestic response has been described in natural killer (NK) cells during cytomegalovirus infection. Experimental studies demonstrated that mouse and human NK cells possess adaptive immune characteristics following infection with mouse cytomegalovirus (MCMV) or human cytomegalovirus, respectively.

Mouse NK cells bearing the Ly49H receptor possess antigen specificity for MCMV-encoded glycoprotein m157 (refs74,75), can undergo clonal proliferation (as much as 104-fold expansion from a single NK cell clone)76,77 and persist during the contraction and memory phases similarly to CD8+ T cells78. On reinfection, these memory NK cells undergo a secondary expansion and can more rapidly degranulate and release cytokines, resulting in a more protective immune response against MCMV.

In human NK cells, the NKG2C receptor can mediate a similar function through recognition of human cytomegalovirus-encoded UL40 peptides presented on the non-classical MHC molecule HLA-E80,81.

Because these adaptive NK cell responses more closely resemble T cell responses than trained immunity in macrophages, yet occur in the absence of RAG-mediated antigen receptor gene rearrangement82, this unique NK cell response may represent an evolutionary bridge between the memory response of T cells and that of myeloid lineage cells78,83.