#bruce ends up finding and adopting mouse like two months later
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witherby · 1 day ago
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In your littlest wayne au (every time I see that I instinctively think of Lil Wayne the rapper lol) there's a very clearly established relationship between Bruce and Hal. I just wanna know how that came to be in that au, I'm curious? Great stuff btw.
FANTASTIC QUESTION. I didn't give it much thought, I just wanted them to be together, but lemme rub my brain cells around real quick
Ok ok, like all good love stories, it starts with a ✨ near-death experience. ✨
I'm imagining a global threat. Some Darkseid-level shit. It takes some back-and-forth and a lot of dumb luck, but eventually the JL snatches a victory from the jaws of defeat.
There's just a couple straggler enemies left. Hal, wounded and low on juice for his ring, doesn't see a bad guy creeping up behind him, so Batman takes the hit and tackles him to the ground. Hal uses the last of the Ring's power to kill the goon, and now he's powerless and clutching a dying Bruce in his arms.
"It's fine," Bruce mumbles, delirious. "Flesh wound. I'll walk it off, I usually do."
"You're telling jokes!? You're about to die and you're telling jokes!?"
"Yeah." Bruce coughs up some blood. He reaches up to thumb away a few flecks that got on Hal's cheek. "I didn't want to die seeing a frown on your pretty face."
Hal clutches his hand and hitches a wet laugh. "You can't confess your love for me on your death bed now that you won't be around for the consequences. That's such an asshole move."
"I'm an asshole. That's a pretty major facet of my personality."
"It's just as much a mask as the cowl is. Shut up."
Bruce shrugs and smiles. Hal keeps firm pressure on the wound and waits for backup to come and help them. In the nick of time, Clark finds them and whisks Bruce off to get medical attention, and it's really touch and go for a couple days before he wakes up to find Hal looking at him very unimpressed.
"You scared the shit out of me. I think I can be forgiven with a date, though. Really fancy one. Wine and dine me."
Bruce just nods sleepily. "What are you doing tonight?"
"YOU JUST WOKE UP? YOU ARE NOT IN ANY SHAPE TO CASH THAT DATE IN RIGHT NOW?"
"Yeah ok... What are you doing tomorrow?"
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mabeljonesrock · 5 years ago
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Hero 108 season 3 AU idea!
My idea of season three:
Few Weeks After Twin masters’s defeat, everything in Hidden Kingdom got better and everyone had tried to rebuild their lives. High Roller and his lackeys suddenly disappeared and aren’t seen again. Animals and humans were now at peace again. Until an unknown Foe arrived in hidden kingdom. Like everyone in hidden kingdom, they are humans and animals. But unlike them, their technology, culture and weapons are much more advanced(think Cyberpunk-steampunk-dieselpunk) and wear futuristic, modern clothes/armor. They come from a different world called the Jin Ping Mei Empire. They attacked the hidden kingdom and many people tried to fight back including Big green. It was a dystopian war and the war last six months. After a intense battle, the tyrannical Jin Ping Mei Empire succeeded into taking over hidden Kingdom and many lives are lost. They captured the remaining humans and animals from hidden kingdom as their slaves. But all hope is not lost for The hidden kingdom. Big green survived but not before losing some of their members to the war and all of them went on a hiding until they find a way to stop The Jin Ping Mei Empire. The first squad and second squad decided to leave Big green and went on a quest to stop the Jin Ping Mei Empire. Three years later, the first squad and second squad return and were now bigger and stronger than ever. They had gain new allies of their own and had new weapons. They band together to stop Jin Ping Mei Empire and Save hidden kingdom once and for all. The Golden Lotus and their cult will be the main villains and were masterminds behind the Jin Ping Mei empire. The golden Lotus will manipulate Ximen Qing(who is the president and ruler of the Jin Píng Mei empire) and he end up becoming their puppet.
1. Jing Ping Mei empire’s culture is based off America, United Kingdom, Japan and China.
2. Ximen Qing is like the Chinese version of Donald trump.
3. Pan Jinlian will appeared in this story and was the love interest of Dog king. But after Dog King’s mysterious death in the Jing Ping Mei Empire, Pan Jinlian blame Big green for not finding his body and not saving him. She left. Three years later, She return for unknown reasons and Told Big green that she had move on her lover’s death and decided to join Big green in honor of her decreased Spouse. Wu song didn’t trust Pan Jinlian because she suspiciously changed His brother’s behavior and habits. Wu Song suspects there something Fishy about her. Pan jinlian’s personality will be sweet, kind, caring and supportive but had notorious motives and plans. She adored Dog king and sometimes treat him like pet puppy. She is very hardworking with her job as a nurse in big green. She is very calm and cool when it come to danger and would not let anger, stress or fear let her. Despite her friendly and innocent exterior, Pan jinlian may or may not had connections to the golden lotus and the children of twin masters
4. Mr Nohands is now a badass cyborg and gain new robotic arms after he forcibly chopped off his hands when his stockade is destroyed during the Jing Ping mei war. After losing his arms and getting new mechanical arms, He decided he done being lazy and now learn to become a more skilled and competent fighter. He is currently the general and second-in-command of ApeTrully.
5. ApeTrully’s secret is accidentally revealed during the Jing Ping mei war. He managed to saved Woo from being killed by Jing Píng Mei soldiers. He survived but it end with him being injured and his disguise is damaged. ApeTrully lose consciousness and is sent to the medic camp where everyone found out he is a monkey when the doctors remove his “clothes” to bandaged his wounds. ApeTrully is ashamed when he realized everyone now know he a monkey. He about to leave big green until Lin Chung and Woo stop him. Everyone in the big green told him they cannot be a rebellion without him being a leader and they didn’t care if he a monkey or not because he still their natural born leader.
6. Glitchout will be voiced by Michaela Dietz or Nina futterman. Missy Metalmice will be voiced by April Winchell. Sandā Will be voiced by Greg Cipes. Pan Jinlian will be voiced by Britt McKillip or Jayma Mays. Ximen Qing will be voiced by Erica Bauza. The golden lotus will remain silent until the end of season 3.
7. For my season 3 idea, Twin masters did get resurrected by the ritual later in series but end up becoming cleansed of his evil thanks to an accident that messed up the ritual. Instead of a malevolent eldritch abomination, standing there was a smol baby Yang Tu with no memories of his past life. The two things he retain from his past is his godly powers and heterochromia eyes(red and blue respectively). The first squad rescued the now amnesiac infant Yang Tu from the children of Twin masters. They decided to adopt and raised him to ensure that he grows up right. They named the baby Yang-ming. Lin Chung will have a soft father-son/brotherly relationship with Yang-Ming and it will be sweet. Everyone in big green decided NOT to reveal Yang Ming’s true identity and had to make sure Yang Ming will not turn evil and make mistakes like his past selves. Despite raising Yang Ming into a sweet and loving kid, Lin Chung start to have nightmares about what happen if Yang Ming regained his memories, become evil again and killed everyone including himself.
8. High Roller and his Lackeys will return in my season 3 au. Like the first and second squad, they come back bigger and stronger and they had become very dangerous crime lords themselves. They gain new allies. The new allies are the five Japanese mad max-inspired mercenaries with the leader being a Ninja-pirate-cowboy-biker named Daisuke who look, speak and fight like Bruce Lee. He be human while The bounty hunters will be Tanuki, Kitsune, Bakeneko and Kappa. They are called The Feral five.
9. The new allies will be a orphan girl, a Kamaitachi who is a ex-member of the feral five(formerly the savage six) and a Mouse who fights in a mecha. The orphan girl will be named Glitchout and serve as the hacker and brains of the trio. She a very spunky and energetic tomboy who enjoy videogames, reading comic books, eating candy and hanging out with her friends. Her abilities is building high tech Weapons/robots, highly skilled in hacking/coding and skilled in street parkour. She a nine year old girl with a bit chubby build and purple wide eyes, pale skin and had shoulder-length hair dyed in Pink, magenta, purple and blue and tied up in low pigtails, Magenta goggles over her head, magenta t-shirt, blue overall shorts, pink and magenta striped tights, a purple hoodie wrapped around her waist, pink fingerless gloves and blue converse boots. Mouse will be named Missy Metalmice and is the brawler of the trio. Despite being a adorable Tiny mouse, she is a fearless and ferocious fighter who is not a person to mess with and will crush her enemy if they poke fun at her height and cute appearance. She hated and cannot stand being treated like a timid, defenseless creature and can be very hotheaded about it. Despite her aloof, stoic and cold exterior, she is a wise, supportive and understanding friend who care for her loved ones and will beat her enemies if they tried to harm them. She serve as a protective but caring mother figure to Glitchout. She is a adorable pink mouse with blue eyes and wear skull earrings, red pink bow, eyeliner and black eyeshadow. Her mecha is seven foot tall, samurai themed and had black and red colour schemes. She had a secret crush on jumpy ghostface. The Kamaitachi will be named Sandā and the speedster of the trio. Despite looking like a fearsome and frightening beast, in reality Sandā is a very kindhearted and friendly pacifist who refused to killed a living being. He is hyperactive, zany and full of energy and enjoy comedy, noodle puns/jokes and games. He is great friends with children. He used to be a rookie member of the Savage six before he defect when he is forced to kill an innocent old lady and her grandchildren. He is a white, yellow and blue Kamaitachi and wear A leather jacket with sleeves ripped off, a golden earring, spiky collar and blue Mohawk.
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sour--strawberries · 7 years ago
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Meow Cafe, part 12
fandom: Stony (Steve x Tony)
universe: Figaro universe, cat cafe!au - Tony works as a barista in a cat cafe and Steve is totally smitten by him and Tony’s overly fluffy cat, Figaro
summary: The big opening of the new Meow Cafe is finally happening!
length: 5 791 words
warnings: this fic belongs to Figaro universe, not focused on tickling, but has some from time to time (some this time)
a/n: FINAL CHAPTER IS HERE! I hope you like it and look at the end for a special surprise! if you enjoyed this series, remember to like, reblog and send me your final thoughts, would love to hear how you liked this love and cat story!
———–
Meow Cafe, part 12
(part 1, part 2, part 3, part 4, part 5, part 6, part 7, part 8, part 9, part 10, part 11)
The work on new Meow Cafe was going smoothly and after another month it was fully furnished and equipped, sparkling new and clean, ready to accept cats and customers. Yet, the final and hardest test remained the one that would define everything.
"He is coming! He is coming!" Janet jumped away from the window, almost entangling herself in the curtains in the process. "The inspector is coming!!" she shrilled, cheeks becoming flushed from the nervous atmosphere.
"Calm down, Jan," Bruce advised, standing behind the bar, next to Pepper who was sipping some coffee.
"What if he won't like the cafe?! What if we did something wrong?! We will have to start all over again!!" Janet panicked further, skipping to Bruce and flailing arms in panic.
"He will like it, we did everything fine---"
"AND WHAT IF WE DIDN'T?!" Janet roared, grabbing Bruce by the collar and almost dragging him out from the bar area. Before Pepper had to intervene, there was a gentle sound of a bell ringing, indicating that someone pushed the door open. The inspector arrived.
"Hi!" Janet immediately let go of Bruce and turned around, her angry scowl turning into a welcoming smile. The girl needed only one second to change her mood dramatically. There was probably some medical term for that, but it wasn't important. "Welcome to Meow Cafe!"
The inspector seemed unfazed. He put his nose up and sniffed, still smelling some of the paint. Tony and Steve walked behind the inspector and smiled nervously at the crew gathered near the bar area.
"Glad you could find time for us," Pepper smiled, greeting their guest. "Janet will show you around," she said, needing to find the over-energetic girl some task, or she might kill them all.
"Of course!" Janet nodded enthusiastically, and the tour started.
The inspector took his time and went meticulously through every inch of Meow Cafe. The new furniture was met with approval, soft and inviting both for cats and humans. The big window had a nice warm spot where the sun was shining, perfect for naps. The new cat shelves were great, placed all over the cafe, with some tunnels between them for double the fun, all in nice, pastel, bright colors and with soft carpet on the top for double kitty comfort. The inspector tested the cat door leading to the cat room, full of cat beds and bowls and more shelves, and a comfy, old couch near the wall, Bruce found on a yard sale. The best was left for last. The playground. It had to be tested to accommodate all kitty needs and shapes and weights and ages, and the inspector examined every toy and shelf and cushion and every scratch pole. It took long, nervous minutes and everyone was getting anxious, trying to hold it in and not rush anything. In the end, the inspector came back to the bar area, looking as mysterious as when the tour started.
"Can I interest you in something to drink?" Janet asked friendly, hoping that it will earn them some additional points.
One, slowly drank, bowl of milk later, the inspector looked around the new cafe and sat his fluffy butt down on the floor. The moment was prolonging and Figaro licked around his mouth, getting the last drops of milk. Immediately, everyone looked to Tony, who had been sitting on the couch with Steve, waiting for translation.
Tony, trying to not choke on his own laughter, knowing how serious everyone was treating the situation, smiled and spread his arms. "He likes it!" he announced.
The Meow Cafe's crew cheered and Figaro closed his eyes in content. Yes, he could imagine his cat friends being comfortable in this new place.
***
"Hi! Welcome! So glad you could come!"
Steve was leaning against the bar and he couldn't keep the smile out of his face. Finally, the day came and it was the grand opening of the new Meow Cafe. Tomorrow, the cafe would be open for all customers while this was the opening for friends and family and people who adopted the cafe's pupils. Steve saw Pepper talking to the older couple, a marriage that had adopted his favorite Little Eye, Blondie and Crazeh, and chatting with the girl with blue eyes and dark bangs, one that gave a home to Shandi. Near the playground and watching the cats inside were three girls plus Janet, excitedly cooing over the cats and commenting how cute they were. Steve didn't know their names, but guessed that the chubby one with long, wavy hair in the middle was the one who adopted Cow, on her right was a girl with asymmetric hair in an unusual rusty orange color, Ariel's owner, and at the left was the one with long blond hair, tied in a bun, and by the hair, Steve made a connection that it was Rapunzel (whose real name still remained unknown), the one who adopted Tsuki. On one of the couches, was Sam and Rhodey, talking to a burly blond, who, as it turned out was neither William or Thud, but Thor, Gizmo's rightful owner, who had brought his brother along, a lanky dark-haired man, staying away from everyone and preferring to put his all attention on the cat in his lap. Steve focused on the cat for a bit. It was a striped tabby with white socks, looking suspiciously similar to Crazeh, although smaller and more muscular, enjoying a long petting session. The new cafe was much bigger than the previous one and could host up to fifteen cats instead of six. Currently, in the cafe was a lucky thirteen of cats. And Steve had to learn the names of all of them.
"That's Cajetan," someone said and Steve looked at Natasha who appeared out of nowhere. As the person who adopted Oliver, she was also invited to the first opening. "He is almost two years old, Bruce says that he is one of the youngest cats here."
Steve nodded and smiled. He could imagine that Bruce was excited as Tony was with all the new cats, but while Tony tend to blab a lot and change from one cat to the other, making it hard to keep track and memorize, Bruce had to be a better source of information.
"Tuma," Natasha pointed up at the cat shelves, where a beautiful tortoiseshell girl was looking down at everyone with her yellow-green eyes. "Pi Shu," on a shelf just below Tuma was another cat, this one resembling Cow a little bit, also black and white and green-eyed, looking at everyone suspiciously, "watch out for her, she gives love bites."
Steve laughed, not at all bothered by kitty love bites. Maybe in the past he did consider it a problem, but not anymore.
"Oh, and there is Zeus," Natasha smiled at the lean cat, a mix of calico and Siamese with unusually bright blue eyes sprinting between their legs to get to the cat's room. "Chased by Little Girl," she laughed, when a grayish-white blur followed Zeus, as both cats were playing with each other. "And there is my favorite, Clawson," Natasha's voice softened and she pointed at the window sill, where stretched out was a big, orange cat, the senior of the group, reaching almost fifteen years old, as finding homes for senior cats was still an important mission for Meow Cafe. Steve saw a resemblance to Oliver and it became clear why this particular cat became Nat's favorite. Maybe if things turn out well, Oliver will get a brother.
"Hey, you almost got them all," Steve looked at his friend, grateful for the short introduction.
"Yeah, almost," Natasha leaned out a little bit, seeing Clint, sitting on the floor and dangling a mouse on a stick in front of two cats, a honey striped cat, and an orange tabby. Izzy and Menina. Izzy was a four years old boy and Menina was an older lady, almost fourteen, but was as playful and energetic as the three times younger Izzy. Clint was laughing and looked perfectly happy, observing cats attempt to get the mice, and sometimes letting them nibble on the toy.
Steve counted the cats they saw so far. Two in the cat's room, six in the cafe area. That meant, that five more were somewhere around. His eyes went to the playground and he saw a small black cat, happily napping on one of the pillows.
"That's Kashi, right?" Steve asked Natasha, trying to remember some of the cats on his own. From what Tony told him, Kashi was a very shy kitty lady and preferred to stay in the playground area, approaching everyone with caution.
"Yeah, it is," Natasha confirmed, and laughed at a gray cat, walking back and forth through one of the tunnels, looking very happy, until the calico one with bright yellow eyes decided to make a surprise and jump on the tunnel, temporarily cutting off the entrance, until the cat wiggled out backwards, to the amusement of the three girls observing the cats. Poor Fezzick, attacked by Lina. Seemed that the younger cats had no respect for their older colleagues. Speaking of younger cats, on numerous fluffy pillows and gently pawing a toy mouse was Amber, gray and with golden eyes, the baby of the cat group, reaching one year. "I think that Celia is also in the playground---"
"Do you need anything?"
"We are good, Bruce," Natasha smiled at her unofficially second boyfriend. Bruce's hair seemed even curlier than usual, as he was rushing in the bar area, pouring coffee after coffee for all of their guests. Even his glasses seemed steamed.
"BRUCE!" Janet roared, appearing suddenly in the bar area, and leaning in to see how the coffee making was going, an empty tray propped against her hip, almost falling to the ground. Immediately, Bruce started to slap her away gently, because Pepper didn't approve of jumping against the sparkly new bar and chipping the paint off. "Our guests need coffee!"
"And we need more cake!" Tony yelled, waltzing past the small group, swiftly collecting empty coffee cups left on the tables. The coffee place was becoming more crowded, as more people who adopted the cats over the two years of Meow Cafe existence were showing up. Pepper basically stood by the door and greeted the new groups, guiding them briefly over the cafe before resuming her position.
"Hi, handsome!"
Steve yelped, and jumped up a little bit, when someone, undoubtedly Tony, while circling and collecting plates and cups, playfully slapped his ass. He only saw Tony's grin as his barista walked away to bus some tables.
"Then you two should come here and help me," Bruce replied through clenched teeth in a deep voice, keeping a low profile, unlike his colleges. Steve had to admit, that the seemingly harmless brunet seemed a lot more threatening out of sudden.
"You have help!" Jan exclaimed, stacking the coffee cups on a tray. "We left you with the new guy!"
New guy? Steve sipped his coffee, looking more alert. Tony didn't tell him that the person who was supposed to fill in for him started the job.
"NEW GUY! Move it!" Jan yelled, almost jumping over the bar and again, but being held back by Bruce.
"I am coming, I am coming!"
The door leading to the kitchen opened, and Steve's eyes widened when he saw a familiar figure with about dozen plates with neatly cut pieces of carrot cake.
"Bucky?!" Steve exclaimed, or would have, if he didn't have a mouthful of coffee and the liquid spilled from his mouth and trickled down his chin. Luckily, Natasha was alert and pressed a napkin to his mouth before any coffee could reach his shirt, but Steve still heard Tony's pearly laughter somewhere in the distance.  For being such a neat person in general, Steve was a huge spiller.
"As for a place that's supposed to be relaxing, you guys are awfully nervous," Bucky grumbled, making his way out of the bar, sporting a Meow Cafe apron worn over black jeans and buttoned shirt, "hi Nat, Steve. Have some cake," Bucky smiled cheekily and slid two plates over the bar. Once again it was up to Natasha to save the moment and catch both plates, as Steve was still too stunned to move.
"Less chit chat more work!" Janet urged, putting some cups of coffee on the empty place on the tray. "Our guests are waiting for coffee! You need to step up your game if you want to work here, you have some big shoes to fill in! Well, metaphorically big shoes, because Tony has tiny feet---"
Steve saw Bucky quickening his pace, clearly escaping from chattering Janet, who followed him closely, talking his ears off. Bucky working at a cat cafe. That was something Steve didn't expect. Clearly, Bucky's fondness for cats ran deeper than Steve thought…
"Let's go and sit," Natasha gently bumped shoulders with Steve's and pushed two plates with cakes into his hands, as she took their coffee. They went to the couch, the same one where Sam, Rhodey and Thor were sitting on, leaving Bruce on coffee duty and giving him some off time. Steve glanced at the back, and saw Tony making his way into the bar area, and taking out clean coffee cups out of the washing machine. Seemed that he won't be able to spend any time with Tony today… After all, it was the opening, a big day for everybody.
When Steve and Natasha made it to the couch, Bucky was serving the last pieces of cake, the very last one going to Sam.
"Saved you the biggest one, doll," he winked at his boyfriend and Sam beamed a proud smile.
"You managed to lose Janet?" Natasha asked with a teasing grin, sitting in the big armchair.
"She stopped to play with Cajetan and talk to that weird, sad kid," Bucky explained.
"That weird kid happens to be my brother," Thor sent Bucky an intimidating look, which lost a lot of threatening power, as the guy stuffed his mouth with carrot cake and had some icing around his lips.
"He is weird," Bucky repeated, totally unfazed.
"I think he is interesting," Natasha smiled, peaking at the man with the small cat in his lap.
"You guys don't seem alike," Steve put in his comment. It was obvious that siblings didn't always resemble each other, but at least they had similarities. Thor, was big and muscled and had a seemingly sunny personality. His brother was smaller in posture, pale and had black hair, and didn't seek company and clearly didn't feel well surrounded by people.
"He is my stepbrother," Thor explained in a small voice, still sounding a bit wounded and sending hurt looks towards Bucky.
"You really shouldn't be the one to judge people! Remember how we met? I gave you five dollars because I thought you were living on the street!" Sam laughed, putting his fork into the carrot cake and taking a bite.
"What?!" everyone exclaimed, as Bucky froze in silent panic.
"You told me you bumped into Sam on a street!" Steve accused Bucky. Another hidden secret. His friend was asking for a long talk.
"You need to tell us!" Natasha smiled wide and evil, crossing her legs for a more comfortable position.
"I am glad to know I wasn't the first one to think he was a homeless guy," Rhodey laughed.
"Believe me, you were not the first one," Steve shook his head. It happened more often than he would like to admit to, but well, that was his best friend.
"There is nothing to tell---" Bucky tried to cut the topic off, but Sam already started.
"I saw him at the subway station. He was sitting on the floor and playing guitar, so I stopped and gave him five dollars to buy himself something warm to eat. And then he used the same five dollars to buy me a coffee--"
"That's basically what I told you!" Bucky explained himself, feeling Steve's angry look.
"You left some parts out," Steve muttered, "and I told you to stop doing that!" he hissed, meaning Bucky's habit of playing guitar in the middle of the city. Bucky claimed that he was entertaining, for Steve, he was asking for trouble. "You will get yourself beaten up one day! Don't walk away when I am talking to you!" Steve kept yelling, as Bucky trotted to serve more coffee, moving his mouth to Steve's words and making faces, mocking him.
"--- and now he has a decent job! My parents keep asking about him and I can finally introduce him!" Sam finished the story, seemingly oblivious to Bucky and Steve's confrontation.
"Guys, better enjoy that carrot cake, we ran out!" Tony called, walking to his group of friends, and collecting the plates and cups he could. "But the honey cake finally cooled down!" he added quickly, noticing Thor's sad puppy look. That guy could eat.
"You started making honey cake again?!" Rhodey called, almost jumping out of his seat. "Dibs on a piece!" he raised his hand up and waved frantically.
"Of course, you will get some, honey bear."
"Oh, so here is the party for all cat people!" someone yelled out.
"Behave," came a deeper and mellow voice.
"Hey, guys! Over here!" Sam raised his hand and waved to the two people standing in the doorway.
It was T'Challa and a friend. They walked to the group, T'Challa in long, broad steps, straight as a board, the other one moved softer, as if almost dancing to some disco music, which wasn't a wrong association as his shirt had a mix logos of old music bands.
"You all know T'Challa already," Rhodey introduced his work colleagues and T'Challa nodded to the group, "and this is Peter," he pointed to the other guy.
"Sup!" Peter clicked his tongue and made a finger gun at the group. He was blond and had some curly hair on top of his head and a light stubble. He was wearing a bomber jacket and jeans, and his style was clearly inspired by the 80s. A total opposite of T'Challa, who was wearing an all black suit, and looked refined and polished. Peter had some rough charm to himself.
"Hi! How is Ramzes?" someone asked, and Steve would focus on that, curious to hear how T'Challa was doing with the loud senior cat, if it wasn't for a whisper next to him.
"Wow, they are hot," Tony gaped at both men, the tray almost slipping out of his hands. What made him grip it back, was Steve's judging look, but what really sent panic down his spine, was the way Rhodey glared at him. Seemed that Tony still didn't learn. "… Hot in here!" Tony corrected himself, closing and opening his mouth in brief panic. "Who wants iced coffee?!" he called into the air, walking away with the tray, cups and plates clinking gently.
Steve should be offended. Yet, at this point, he only smiled to himself and shook his head at his boyfriend's behavior.
"Don't worry," Rhodey said and Steve looked at him, as Rhodey picked up some of the plates Tony left behind, "I know when that idiot is really in love," he stood up, and went to put the plates away.
Steve kept smiling and looked at the piece of carrot cake he was handed earlier, feeling something warm inside. He focused on that and started eating, listening to his friends talking.
***
"Sit down!"
"But---"
"You were standing for the whole day! Sit down!"
"But we need---"
"SIT. DOWN!!"
Pepper raised her hands up in a desperate gesture. Not having any other choice, she plopped down on the couch, obediently staying where her crew had pointed her to. "Here. I am sitting, happy?"
"Yes," Janet beamed, as Bucky and Bruce were cleaning the cafe, joined by Sam, Rhodey and Steve. "We will handle it, you rest!" Janet decided, walking away with Natasha to collect plates and cups from the tables. Clint and Tony were nowhere to be seen, but that probably meant that they were back in the cats' room, refilling the bowls with food and water and cleaning the litter boxes for the night.
The cafe was emptying, their guests already had left and cats were nestling for a night of sleep. Tomorrow would be a new day and cafe would function normally, ready to serve more guests and look for homes for the new cats.
"Did you count the cats?!" Pepper turned around from her place on the couch, when Tony and Clint walked out from the bar area.
"Six!" Tony called back, "seven more to find!"
"I am on it!" Clint took the job and walked to the playground area, ready to play 'spot the cat'.
"Before we turn the bar off, does anyone want something?! Coffee, tea?!" Bruce called and collected some orders, while the rest was cleaning. It didn't take long to clean with so many helpers, and soon the cafe became spotless again, ready for tomorrow.
"Thanks, guys. You all did a great job today," Pepper smiled gratefully as her crew and friends sat around her and the group enjoyed a last cup of coffee, mugs handed out by Clint and Janet.
"Milady, your coffee," Clint said charmingly, offering Natasha a cup of black and strong coffee. "As black and bitter as your soul, just the way you like it," he added with a cheerful grin and Natasha cooed a thank you, taking the cup and gesturing towards Bruce to join them.
Steve held his latte and Tony's double espresso and looked around for his boyfriend. He saw him at the other end of the cafe, alone and standing in front of the colorful wall. Steve made his way there, not recalling such colorful wall being in the cafe. Soon, it all made sense. He joined Tony and smiled at the black wall with photos all cats that had ever been adopted from Meow Cafe, in their forever homes, each photo signed by the owner in a colorful marker. Cow, Ariel, Tsuki, Crazeh… They were all there, including some cats Steve didn't have an occasion to meet. There were also current cats's photos on the wall, ready for adoption and looking for their humans. Steve remembered Meow Cafe guests crowding in this spot earlier, but didn't know why. It was a great memento and a tribute.
"That's incredible," Steve smiled, looking at Tony with love. "You helped all those cats, you know that? You helped them find a home," he said and he couldn't possibly love Tony anymore.
"I had some help," Tony answered and turned to Steve, smiling and a bit teary eyed. Thinking about his former pupils, always made him emotional. The mood changed drastically when he noticed what Steve was holding. "Is that a latte?!" he gasped out in horror, looking at the cup.
"Um… Yeah, but don't worry, it is for me, I have an espresso for you---"
"You have been drinking lattes the whole evening?!"
"Yes?"
"The hell--- BRUCE!!" Tony called, leaning out from behind Steve and looking at his group of friends, "you have been serving Steve lattes?! Regular or soy milk?! REGULAR OR SOY?!"
Bruce didn't answer. The way he curled between Natasha and Clint was an answer in itself. Hey, it was a busy night. He forgot. Bucky tsked and shook his head. It wasn't a secret that Steve was lactose intolerant, yet, sometimes it seemed that Steve was the one who forgot most often.
"Oh God," Tony whined, hiding face in his hands and after a while glaring at Steve through his fingers. "You are so not sleeping in my bed tonight!"
Steve couldn't help it. Tony looked so indignant and mad, he had to put the coffee on the nearby table, as he started to shake with silent laughter and it was hard to keep the cups steadily in his hands.
"I am serious!" Tony shrilled, pointing an accusing finger at Steve and not understanding what was so amusing about this situation, "last time you had milk, Fig was terrified! It was like an all-night artillery shooting!"
Steve did the only thing he could in this situation. He hugged wriggling Tony close and kept laughing until his hotheaded boyfriend ended his tantrum.
***
It was a week after the opening of the Meow Cafe and everything was going smoothly. Bucky got the job, and happily served coffee and took care of the cats, under Janet's watchful eye, whose enthusiasm and passion earned her the main barista title, that previously belonged to Tony. Sam finally introduced his parents to Bucky, inviting them to the Meow Cafe one evening. Bruce, Natasha and Clint could be seen more often together, becoming more open about their relationship. Even Rhodey finally bought an apartment in New York and could regularly meet with Pepper and Tony, without taking their friends' couch for the night. But most importantly, new cats were bonding with new people and had chances to find their forever homes. Soon, Meow Cafe had the first adoption and it was Peter, the guy T'Challa brought for the opening, who was the first one to adopt a cat and Cajetan found his forever home. And Tony and Steve kept working and being in a relationship and loved each other and possibly couldn't be happier.
Everything was just fine.
Just. Fine.
Fine.
Fine?
It was wrong.
Something was horribly, horribly wrong.
"Ah… Ah!! Hah!!"
"Meow!!"
"Tony…"
"Nghhh… No, don't--- AH!"
"MEOW!!"
It was wrong, wrong, wrong. His human was crying and it sounded like if he was in pain and he didn't know why. He needed to help him. Figaro started to frantically scratch on the locked door, needing to get inside. He needed to protect his friend.
"HAH! Ah ah ah!!"
"MEEEOOOW!!!"
"Tony!!"
"Yghhhh OKAY FINE!"
The door suddenly opened, and before Figaro could slide inside and attack with sharp claws whoever was hurting his friend, he was hoisted up and carried away, pressed to bare, human skin. Figaro blinked at that and saw the room moving and instead of being in the corridor, he suddenly found himself in the bathroom.
"Fiiiiig," Tony whined, locking the door and putting the cat down. Figaro immediately brushed around his human's legs, relieved to see that he was fine, although the lack of clothing and raised body temperature was a bit alarming.
"Yeah, yeah, I love you too, but Fig!" Tony snapped his fingers and crouched down to get to a more or less the same eye level as his cat, "focus now! Remember the talk we had?"
Figaro sat his fluffy butt down, looking at his human. They had many talks. He should be more specific. Humans were so unreasonable sometimes.
"The first one?" Tony emphasized. "The very first one? Come on, I know you can remember."
The first one…
Ooohh…
Figaro remembered. It was a long time ago. A very long time ago, when his hind paw was hurting and everything, including his human, seemed a lot bigger and scarier.
"We are here! This is where you live now!"
He looked around, seeing an unknown, big place. It was big, but also warm. He liked warm.
"This is where you will eat. Here I will put a litter box for you. And here is where we will sleep!"
His bright eyes followed, trying to take everything in. It seemed like a lot, but he would handle it.
"Oh, but first thing first…"
The human sat down and kept him on his lap. It was warm and soft, and he suddenly felt very sleepy.
"Listen," the human said, and stroked a single finger along his head and he closed his eyes in content. That felt nice. "I promise to keep you healthy, well fed and safe, and when the time comes, I will help you move on as quickly and painlessly as possible," the human said, sounding serious and he opened his eyes, feeling that it was an important moment, "in return, you will do your stuff into the litter box, won't wake me up at nights and allow me to get laid when I bring someone home, okay?"
A tiny meow. Not quite an agreement, as he didn't understand most of the words, but it seemed important to his human.
"Okay," human smiled, and scratched behind his ears. Nice. "You need a name…" human said, looking at him with a thoughtful face. "Can't think without music. Gimme a sec," human continued and slid the kitten gently off his lap, walking away. He didn't move away, when some loud noise filled the apartment and he curled in himself, eyes widening up in fear.
"Ooops, sorry!" human amended, making the noise quieter. It was a sound he never heard before. It was like screaming, but there was some pattern to it.
"You okay, buddy?" human asked sympathetically and sat back on the couch, taking him back in his lap. He continued to curl, alerted by the sound. Somehow it reminded him of his time outside, but it was different. He was safe now.
"My mom used to listen to this all the time," human said, closing his eyes and stroking a gentle hand along his back, remembering. It had to be a fond memory and he felt the happy vibes the person was giving.
"Meow," he said quietly, reminding of his presence.
"Hm? You like it too?" that's not exactly what the meow stand for, but he would train the human with time to better understand him. "Okay, so… How about Figaro? Do you like it as a name?"
"Meow!"
The human smiled and he felt he made something good happen. "Then it is settled. This will be your new name. Figaro!" 
During the years, Figaro tried to keep most of the promises. Yet, he felt scolded and lowered his beautiful head in shame.
"I knew you can remember."
Hmm, so get laid mean mating. A cat learns something new every day. He interrupted his humans mating. At least he knew it wasn't pain and could calm down.
"Okay, we will do it like this," Tony decided and Figaro saw bare feet walking away. Tony opened the closet under the sink where he kept the clean towels and put some out, for Figaro to squeeze in if he would decide to, and poured some water into the sink, in case if the cat got thirsty. Not the best conditions, but it would do for a while and he saw Figaro licking off droplets of water from the sink numerous times already, so it shouldn't be that bad.
"I will let you out soon, okay?" Tony said, petting his cat's head and walking to the door. Figaro closed his eyes, giving his human a permission to leave. Quietly, Tony slid out and closed the door. Figaro looked around the spacious bathroom and decided to nap for the time being. He walked to the closet and threw out with his paw some more of the towels and squeezed inside, curling into a little ball in the tight space. Purrfect.
***
It was so warm and nice. He was cuddled into a warm person and there was a hand scrubbing his head. He was practically melting.
Tony purred playfully at the morning affection, letting the other man know, that he was slowly wakening up. The scrubbing stopped for a moment and then continued with tender care.
"Good morning," Steve whispered, pressing lips to brunet's curly hair.
"Morning," Tony answered, stretching his legs and sinking back into Steve, not bothering to open his eyes. It was just too sweet to move and he could still feel the afterglow from the long, hot night they had.
"I have to get up," Steve said, moving his fingers to stroke along Tony's nape.
"No, you don't," Tony argued, not keen on letting his personal heater go.
"Yes, I do," Steve argued back and smiled, gently moving away and pressing kisses into Tony's face and tickling his ribs and sides gently when the stubborn brunet still didn't want to let go. Giggling and breathless, Tony dropped back into the bed and stayed entangled in the covers, smiling sweet and in love, getting the same smile back from the blond.
"I will get some lunch for us on way back," Steve promised, leaning down and kissing his boyfriend. Never enough of kisses. "And you can stay in bed and cuddle with Figaro now."
Tony scrunched his nose. Seeing that Steve mentioned him… Why their cat wasn't in bed with them? Figaro should be already between them and taking up space, instead they had a nice morning and woke up cuddled to each other---
Oh, son of a---
Steve almost fell off the bed, alarmed by the loud wheeze and the way Tony rushed out, bare feet running on the wooden floor. He heard him stopping in the corridor and opening the door loudly, almost ripping it out of the hinges.
"FIGARO!!" Tony called in real panic, as if spending half of the night in a closed bathroom, would scar his cat horribly. Figaro calmly peaked out his head from among the towels, happily sleeping in warmth and peace. Humans had to be always so loud.
"FIG, I AM SO SORRY!" Tony scrambled to his cat and took him out from among the towels and hugged close to his chest, cradling him in his arms. "MY POOR BABY!"
"Is Fig okay?!" Steve called from the bedroom, feeling alarmed by the cries, but also knowing that Tony could be overdramatic sometimes.
"NO THANKS TO YOU!" Tony yelled, deeply offended. "YOU MADE ME LOCK MY BABY AWAAAY!"
Steve raised his eyes to the ceiling. Drama, drama, drama. He would have to buy a package of bacon and a box of donuts on his way home to placate both Figaro and Tony.
So, this was what his life became…
He wouldn't trade it for the world.
And with that thought he went to the kitchen to prepare a breakfast for all of them, smiling on his way.
<-- previous chapter
thank you for loving this series and thank you to my friends and readers for letting me borrow their cats! look below for a surprise!
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orbemnews · 4 years ago
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Researchers Are Hatching a Low-Cost Coronavirus Vaccine A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make. Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world. If NVD-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NVD-HXP-S for themselves or acquire it at low cost from neighbors. “That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center. First, however, clinical trials must establish that NVD-HXP-S actually works in people. The first phase of clinical trials will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects. “It’s a home run for protection,” said Dr. Bruce Innes of the PATH Center for Vaccine Innovation and Access, which has coordinated the development of NVD-HXP-S. “I think it’s a world-class vaccine.” 2P to the rescue Vaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein. Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them. In the case of the coronavirus, the best target for the immune system is the protein that covers its surface like a crown. The protein, known as spike, latches onto cells and then allows the virus to fuse to them. But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies. This insight emerged long before the Covid-19 pandemic. In 2015, another coronavirus appeared, causing a deadly form of pneumonia called MERS. Jason McLellan, a structural biologist then at the Geisel School of Medicine at Dartmouth, and his colleagues set out to make a vaccine against it. They wanted to use the spike protein as a target. But they had to reckon with the fact that the spike protein is a shape-shifter. As the protein prepares to fuse to a cell, it contorts from a tulip-like shape into something more akin to a javelin. Scientists call these two shapes the prefusion and postfusion forms of the spike. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don’t stop it. Dr. McLellan and his colleagues used standard techniques to make a MERS vaccine but ended up with a lot of postfusion spikes, useless for their purposes. Then they discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline. The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus. The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans. But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike. Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike. Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year. Two prolines are good; six are better Dr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.” Updated  April 5, 2021, 4:37 a.m. ET But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more. “It made sense to try to have a better vaccine,” said Dr. McLellan, who is now an associate professor at the University of Texas at Austin. In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations. The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. Dr. McLellan called the new spike HexaPro, in honor of its total of six prolines. The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine. Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines. “The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said. To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties. Meanwhile, Dr. Innes and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own. With a little help from eggs The first wave of authorized Covid-19 vaccines require specialized, costly ingredients to make. Moderna’s RNA-based vaccine, for instance, needs genetic building blocks called nucleotides, as well as a custom-made fatty acid to build a bubble around them. Those ingredients must be assembled into vaccines in purpose-built factories. The way influenza vaccines are made is a study in contrast. Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines. The PATH team wondered if scientists could make a Covid-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make Covid-19 shots as well. In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans. For years, scientists had been experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes. The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins. At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S. PATH arranged for thousands of doses of NDV-HXP-S to be produced in a Vietnamese factory that normally makes influenza vaccines in chicken eggs. In October, the factory sent the vaccines to New York to be tested. The Mount Sinai researchers found that NDV-HXP-S conferred powerful protection in mice and hamsters. “I can honestly say I can protect every hamster, every mouse in the world against SARS-CoV-2,” Dr. Peter Palese, the leader of the research, said. “But the jury’s still out about what it does in humans.” The potency of the vaccine brought an extra benefit: The researchers needed fewer viruses for an effective dose. A single egg may yield five to 10 doses of NDV-HXP-S, compared to one or two doses of influenza vaccines. “We are very excited about this, because we think it’s a way of making a cheap vaccine,” Dr. Palese said. PATH then connected the Mount Sinai team with influenza vaccine makers. On March 15, Vietnam’s Institute of Vaccines and Medical Biologicals announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S. Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form. To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok. In Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.” Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.” Madhavi Sunder, an expert on intellectual property at Georgetown Law School, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said. Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said. In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro. “There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’” Source link Orbem News #coronavirus #Hatching #lowcost #Researchers #Vaccine
0 notes
orbemnews · 4 years ago
Link
Researchers Are Hatching a Low-Cost Coronavirus Vaccine A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make. Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world. If NVD-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NVD-HXP-S for themselves or acquire it at low cost from neighbors. “That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center. First, however, clinical trials must establish that NVD-HXP-S actually works in people. The first phase of clinical trials will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects. “It’s a home run for protection,” said Dr. Bruce Innes of the PATH Center for Vaccine Innovation and Access, which has coordinated the development of NVD-HXP-S. “I think it’s a world-class vaccine.” 2P to the rescue Vaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein. Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them. In the case of the coronavirus, the best target for the immune system is the protein that covers its surface like a crown. The protein, known as spike, latches onto cells and then allows the virus to fuse to them. But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies. This insight emerged long before the Covid-19 pandemic. In 2015, another coronavirus appeared, causing a deadly form of pneumonia called MERS. Jason McLellan, a structural biologist then at the Geisel School of Medicine at Dartmouth, and his colleagues set out to make a vaccine against it. They wanted to use the spike protein as a target. But they had to reckon with the fact that the spike protein is a shape-shifter. As the protein prepares to fuse to a cell, it contorts from a tulip-like shape into something more akin to a javelin. Scientists call these two shapes the prefusion and postfusion forms of the spike. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don’t stop it. Dr. McLellan and his colleagues used standard techniques to make a MERS vaccine but ended up with a lot of postfusion spikes, useless for their purposes. Then they discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline. The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus. The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans. But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike. Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike. Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year. Two prolines are good; six are better Dr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.” Updated  April 5, 2021, 4:37 a.m. ET But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more. “It made sense to try to have a better vaccine,” said Dr. McLellan, who is now an associate professor at the University of Texas at Austin. In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations. The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. Dr. McLellan called the new spike HexaPro, in honor of its total of six prolines. The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine. Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines. “The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said. To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties. Meanwhile, Dr. Innes and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own. With a little help from eggs The first wave of authorized Covid-19 vaccines require specialized, costly ingredients to make. Moderna’s RNA-based vaccine, for instance, needs genetic building blocks called nucleotides, as well as a custom-made fatty acid to build a bubble around them. Those ingredients must be assembled into vaccines in purpose-built factories. The way influenza vaccines are made is a study in contrast. Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines. The PATH team wondered if scientists could make a Covid-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make Covid-19 shots as well. In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans. For years, scientists had been experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes. The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins. At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S. PATH arranged for thousands of doses of NDV-HXP-S to be produced in a Vietnamese factory that normally makes influenza vaccines in chicken eggs. In October, the factory sent the vaccines to New York to be tested. The Mount Sinai researchers found that NDV-HXP-S conferred powerful protection in mice and hamsters. “I can honestly say I can protect every hamster, every mouse in the world against SARS-CoV-2,” Dr. Peter Palese, the leader of the research, said. “But the jury’s still out about what it does in humans.” The potency of the vaccine brought an extra benefit: The researchers needed fewer viruses for an effective dose. A single egg may yield five to 10 doses of NDV-HXP-S, compared to one or two doses of influenza vaccines. “We are very excited about this, because we think it’s a way of making a cheap vaccine,” Dr. Palese said. PATH then connected the Mount Sinai team with influenza vaccine makers. On March 15, Vietnam’s Institute of Vaccines and Medical Biologicals announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S. Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form. To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok. In Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.” Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.” Madhavi Sunder, an expert on intellectual property at Georgetown Law School, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said. Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said. In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro. “There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’” Source link Orbem News #coronavirus #Hatching #lowcost #Researchers #Vaccine
0 notes