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Saturday, May 1, 2021

COVID infections and deaths after 1st shot are rare: UK study

 A very small number of mainly frail, elderly COVID-19 patients are being hospitalised and dying even after having a first dose of Pfizer's or AstraZeneca's vaccines, but this does not mean the shots aren't working, UK researchers said on Friday.

Presenting real-world data on a subset of hospitalised COVID-19 patients in the UK, the researchers said the findings showed some level of "vaccine failure" - in other words cases where vaccinated people still become infected and get sick - but that this was "not unexpected."

"It's mostly occurring in the group which are most at risk of severe disease anyway, which is the elderly. These people are very frail and very elderly," said Calum Semple, a University of Liverpool professor of child health and outbreak medicine, who co-led the research.

"We're not saying the vaccine doesn't work," he told a briefing. "In fact this is good real-world evidence of it working. But it also shows that the vaccine isn't perfect."

The data, published as a preprint on Friday without having been peer-reviewed, showed that among just over 52,000 hospitalised COVID-19 patients studied, 526 had been vaccinated with a first dose of either the AstraZeneca or Pfizer shot at least three weeks earlier. Of those, 113 died.

The vast majority of the post-vaccination COVID-19 cases and fatalities were among vulnerable, elderly people, the researchers said.

AstraZeneca's (AZN.L) COVID-19 vaccine has been shown in clinical trials to be 76% effective against severe disease, while trials of the Pfizer (PFE.N) shot found more than 90%efficacy. read more

Using first the Pfizer and then also AstraZeneca vaccines, Britain has one of the fastest COVID-19 vaccine rollouts in the world - with more than 33.8 million first doses given so far and a quarter of adults receiving two doses.

Earlier this month, Public Health England said the rollout had prevented more than 10,000 deaths of people aged 60 and older by the end of March. read more

Peter English, a specialist in communicable disease control, said the findings released on Friday confirmed "that the vaccine is not 100% effective" and were consistent with other data showing the overall positive impact of Britain's vaccination programme.

https://www.reuters.com/business/healthcare-pharmaceuticals/post-vaccine-covid-infections-deaths-rare-uk-study-finds-2021-04-30/

Friday, April 30, 2021

Werewolf Therapeutics (HOWL) IPO Opens 14% Higher

 Today's IPO for Werewolf Therapeutics, Inc. (NASDAQ: HOWL) opened for trading at $18.21 after pricing 7,500,000 shares of common stock at a public offering price of $16.00 per share.

Jefferies, SVB Leerink and Evercore ISI are acting as joint book-running managers for the offering. H.C. Wainwright & Co. is acting as lead manager for the offering.

Werewolf Therapeutics, Inc. is an innovative biopharmaceutical company pioneering the development of therapeutics engineered to stimulate the body’s immune system for the treatment of cancer. We are leveraging our proprietary PREDATOR™ platform to design conditionally activated molecules that stimulate both adaptive and innate immunity with the goal of addressing the limitations of conventional proinflammatory immune therapies. Our INDUKINE™ molecules are intended to remain inactive in peripheral tissue yet activate selectively in the tumor microenvironment. Our most advanced product candidates, WTX-124 and WTX-330, are systemically delivered, conditionally activated Interleukin-2 (IL-2), and Interleukin-12 (IL-12) INDUKINE molecules for the treatment of solid tumors. We are continuing preclinical studies for both WTX-124 and WTX-330 and expect to advance each candidate in multiple tumor types as a single agent and in combination with an immune checkpoint inhibitor.

https://www.streetinsider.com/IPOs/Werewolf+Therapeutics+%28HOWL%29+IPO+Opens+14%25+Higher/18341471.html

SARS-CoV-2 sculpts immune system to induce sustained virus-specific naïve-like and memory B cell responses

 Leire de Campos-Mata, Sonia Tejedor Vaquero, Roser Tachó-Piñot, Janet Piñero, Emilie K. Grasset, Itziar Arrieta Aldea, Natalia Rodrigo Melero, Carlo Carolis, Juan P. Horcajada, Andrea Cerutti, Judit Villar-García, 

Giuliana Magri

Prior SARS-CoV-2 infection rescues B, T cell responses to variants after 1st vaccine dose

 Catherine J. Reynolds1,, 

  1. Corinna Pade2,
  2. Joseph M. Gibbons2,
  3. David K. Butler1
  4. Ashley D. Otter3
  5. Katia Men
    1. DOI: 10.1126/science.abh1282
      1. PDF: 
    2. https://science.sciencemag.org/content/early/2021/04/29/science.abh1282/tab-pdf

        Abstract

        SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

        https://science.sciencemag.org/content/early/2021/04/29/science.abh1282

1/3 of kids develop a mental health problem after concussion

 A third of children and adolescents develop a mental health problem after a concussion, which could persist for several years post-injury, according to a new literature review.

The research, led by the Murdoch Children's Research Institute (MCRI) and published in the British Journal of Sports Medicine, found mental health should be evaluated as part of standard pediatric concussion assessment and management.

MCRI researcher and Monash University PhD candidate Alice Gornall said despite many post-concussion and mental health symptoms overlapping, the relationship between delayed recovery and mental health had remained poorly understood until this literature review.

The review of 69 articles published between 1980 to June 2020, involved almost 90,000 children, aged 0-18 years, from nine countries including Australia, US, Canada and New Zealand, who had a concussion. Falls (42.3 per cent) and sporting injuries (29.5 per cent) were the most common cause of injury, followed by car accidents (15.5 per cent).

It found up to 36.7 per cent experienced significantly high levels of internalising problems such as withdrawing, anxiety, depression and post-traumatic stress and 20 per cent externalising problems such as aggression, attention problems and hyperactivity after concussion compared with healthy children or children who sustained other injuries such as an arm fracture.

Pre-existing mental health problems were a strong predictor of post-concussion mental health issues. The review stated 29 per cent of children with a pre-injury mental health diagnoses received a new mental health diagnosis post-concussion. Up to 26 per cent without prior mental health problems went onto develop symptoms.

Ms Gornall said while significant improvements in mental health emerged between three and six months post-injury, a minority of children experienced persisting symptoms for several years afterwards.

The findings come after a recent study, led by MCRI and published in The Journal of Head Trauma Rehabilitation, found having a traumatic brain injury in early childhood was associated with lower IQ scores that persist up to seven years post-injury.

Ms Gornall said concussion was a growing public health concern with a third of children experiencing a head injury before 13 years of age.

"Despite the high incidence of concussion among children and adolescents, identifying those at risk of ongoing difficulties after concussion remains a prominent challenge for clinicians," she said.

"On top of this, children take twice as long to recover from concussion than adults, with one in four children experiencing symptoms beyond one-month post-injury."

Melbourne resident Emma, 17, has been seeking mental health support after suffering two concussions, a year apart.

In 2019 while playing netball she knocked her head on a goal post and last March she was hit with a ball in the back of the head.

Emma said after the second concussion she developed anxiety, headaches, a sense of hopelessness and had trouble concentrating.

"After my last concussion I found it very hard to be motivated for school and everyday life. Doing the simplest of tasks such as a walk was difficult for me, not being able to complete these tasks got me quite disheartened which impacted on my mental health," she said.

Emma's dad Bruce Henry said he welcomed the push for mental health to be part of paediatric concussion assessment and management as many cases would be going untreated.

"When a child has a concussion they might look fine but you can't see the underlying impact," he said. It's so important for mental health to form part of concussion management, which has been essential to Emma's recovery process."

MCRI researchers are also trialling an intervention, Concussion Essentials, to prevent children suffering long term post-concussion symptoms.

The eight session intervention combines physiotherapy and psychology treatments that target presenting symptoms with education around common concerns such as headache, fatigue and return to exercise, school and sports. Early data shows that the intervention is effective in accelerating recovery.

MCRI Professor Vicki Anderson said assessment, prevention and intervention of mental health difficulties after concussion should be integrated into standard concussion management.

"Mental health is central to concussion recovery. Concussion may both precipitate and exacerbate mental health difficulties, impacting delayed recovery and psychosocial outcomes," she said.

"Incorporating mental health risk into post-injury management represents an opportunity to engage children and adolescents with mental health services to either prevent unnecessary problems emerging or to treat already existing issues."

Developed by world-leading concussion experts at MCRI and The Royal Children's Hospital and in collaboration with the AFL, the HeadCheck app also helps parents, coaches and first aiders to recognise the signs of concussion and manage the child's safe return to school, play and organised sport.


Story Source:

Materials provided by Murdoch Childrens Research InstituteNote: Content may be edited for style and length.


Journal Reference:

  1. Alice Gornall, Michael Takagi, Thilanka Morawakage, Xiaomin Liu, Vicki Anderson. Mental health after paediatric concussion: a systematic review and meta-analysisBritish Journal of Sports Medicine, 2021; bjsports-2020-103548 DOI: 10.1136/bjsports-2020-103548

How diet controls RNA maturation

 Particularly sensitive to chemical modifications, messenger RNAs (mRNAs) are molecules responsible for transmitting the information encoded in our genome, allowing for the synthesis of proteins, which are necessary for the functioning of our cells. Two teams from the University of Geneva (UNIGE), Switzerland, in collaboration with the Norwegian University of Science and Technology (NTNU), have focused on a specific type of chemical modification -- called methylation -- of mRNA molecules in the small worm Caenorhabditis elegans. They found that methylation on a particular sequence of an mRNA leads to its degradation and that this control mechanism depends on the worm's diet. These findings are to be read in the journal Cell.

Several steps take place before a DNA-encoded gene produces the corresponding protein. One of the two strands of DNA is first transcribed into RNA, which then undergoes several processes, including splicing, before being translated into a protein. This process removes unnecessary non-coding sequences (introns) from the gene, leaving only the protein-coding sequences (exons). This mature form of RNA is called messenger RNA (mRNA).

A "post-it" to block protein synthesis

In addition to these processes, RNA -- but also DNA molecules -- can undergo a chemical modification: methylation. This consists in adding a methyl group (CH3) which allows to modify the fate of these molecules without altering their sequence. Deposited on the RNA or DNA in very specific places like "post-its," methyl groups indicate to the cell that a particular fate must be given to these molecules. Methylation of RNA is essential: mice without RNA methylation die at an early embryonic stage.

Two neighboring teams at the UNIGE, one working on RNA regulation and the other specializing in DNA organisation in the worm C. elegans, have studied the role of methylation in controlling gene expression. The laboratories of Ramesh Pillai and Florian Steiner, professors in the Department of Molecular Biology at the UNIGE Faculty of Science, have shown for the first time that methylation at the end of the intron of a particular gene blocks the splicing machinery. The intron cannot be removed and the protein is not produced.

Fine regulation to ensure a fair balance

This gene, whose mRNA is modified by methylation, encodes for the enzyme that produces the methyl donor. "It is therefore a self-regulating mechanism since the gene involved in producing a key factor required for methylation is itself regulated by methylation!," explains Mateusz Mendel, a researcher in the Department of Molecular Biology at the UNIGE Faculty of Science, and the first author of this study.

Moreover, this modification is dependent on the quantity of nutrients received by the worms. "When nutrients are abundant, the mRNA is methylated, gene splicing is blocked, and the level of methyl donors decreases, which limits the number of possible methylation reactions. On the other hand, when there are few nutrients, there is no methylation of the particular RNA of this gene, so splicing is not blocked and the synthesis of methyl donors increases," reports Kamila Delaney, a researcher in the Department of Molecular Biology at the UNIGE Faculty of Science. Elements present in the food provide the raw materials required for producing the methyl donor, so methylation-dependent splicing inhibition puts a brake on its production under conditions of a rich diet. "Aberrant methylation reactions -- too much or too little -- are the cause of many diseases. The cell has set up this very sophisticated regulatory system to ensure a fair balance of methylations in the cell," summarizes Mateusz Mendel.

Methylation of mRNAs at these specific sequences was discovered in the 1970s by scientists, including Ueli Schibler, a former professor at the UNIGE, before being forgotten. It took 40 years before researchers rediscovered its importance in gene regulation in 2012. With this study, scientists from the Department of Molecular Biology highlight the crucial role of methylation in the control of splicing and in the response to environmental changes.


Story Source:

Materials provided by Université de GenèveNote: Content may be edited for style and length.


Journal Reference:

  1. Mateusz Mendel, Kamila Delaney, Radha Raman Pandey, Kuan-Ming Chen, Joanna M. Wenda, Cathrine Broberg Vågbø, Florian A. Steiner, David Homolka, Ramesh S. Pillai. Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicingCell, 2021; DOI: 10.1016/j.cell.2021.03.062