the colossus of new york book review

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THE COLOSSUS OF NEW YORK

A city in thirteen parts.

by Colson Whitehead ‧ RELEASE DATE: Oct. 21, 2003

Poetry in paragraphs.

As ebullient as Walt Whitman and as succinct as Emily Dickinson, a young novelist ( John Henry Days , 2001, etc.) looses his five senses on his native New York City—and allows the sixth some play, as well.

Whitehead makes it both difficult and easy for readers in this astonishingly evocative view of Gotham. The difficulties all arise from his poetic language. He eschews question marks, commas, and much other interior punctuation, as if to say, “Slow down. You don’t need that stuff to understand me.” And his paragraphs will drive pedantic grammarians wild (even as they will delight the liberated), for he segues smoothly from first person to second to third—in both singular and plural—as if to ask (without the question mark and comma, of course), “Hey, what’s the difference?” And yet . . . reading him is as natural (and as uncomfortable) as looking in a full-length mirror. It’s as if Whitehead has heard all of our conversations, smelled our fears, tasted our successes, recognized our falseness, tapped our phones and our fantasies, and, yes, felt our pain. The volume comprises 13 short pieces that have both a loose chronological and a cyclical sense: morning to night, arrival and departure, birth and death. Near the beginning is a piece about the Port Authority bus station that deals with bus rides, uncertainties, stresses, and arrivals in the New World of Manhattan. Near the end is a snippet about a departure from Kennedy Airport; in the air, you look back over the city, says Whitehead, and you see such a vast expanse that “you realize you were never really there at all.” In between are riffs on Central Park, the subway, rain, Broadway, Coney Island, the Brooklyn Bridge, and so on. And rippling just underneath the surface of many of the pieces are a certain sexual energy (a firm nipple here, an erection there) and some unobtrusive allusions to 9/11 (on the Brooklyn Bridge: “If it shakes it can fall”).

Pub Date: Oct. 21, 2003

ISBN: 0-385-50794-1

Page Count: 128

Publisher: Doubleday

Review Posted Online: May 19, 2010

Kirkus Reviews Issue: July 15, 2003

GENERAL NONFICTION

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BOOK REVIEW

by Colson Whitehead

by E.T.A. Hoffmann ‧ RELEASE DATE: Oct. 28, 1996

This is not the Nutcracker sweet, as passed on by Tchaikovsky and Marius Petipa. No, this is the original Hoffmann tale of 1816, in which the froth of Christmas revelry occasionally parts to let the dark underside of childhood fantasies and fears peek through. The boundaries between dream and reality fade, just as Godfather Drosselmeier, the Nutcracker's creator, is seen as alternately sinister and jolly. And Italian artist Roberto Innocenti gives an errily realistic air to Marie's dreams, in richly detailed illustrations touched by a mysterious light. A beautiful version of this classic tale, which will captivate adults and children alike. (Nutcracker; $35.00; Oct. 28, 1996; 136 pp.; 0-15-100227-4)

Pub Date: Oct. 28, 1996

ISBN: 0-15-100227-4

Page Count: 136

Publisher: Harcourt

Kirkus Reviews Issue: Aug. 15, 1996

More by E.T.A. Hoffmann

by E.T.A. Hoffmann ; adapted by Natalie Andrewson ; illustrated by Natalie Andrewson

by E.T.A. Hoffmann & illustrated by Julie Paschkis

TO THE ONE I LOVE THE BEST

Episodes from the life of lady mendl (elsie de wolfe).

by Ludwig Bemelmans ‧ RELEASE DATE: Feb. 23, 1955

An extravaganza in Bemelmans' inimitable vein, but written almost dead pan, with sly, amusing, sometimes biting undertones, breaking through. For Bemelmans was "the man who came to cocktails". And his hostess was Lady Mendl (Elsie de Wolfe), arbiter of American decorating taste over a generation. Lady Mendl was an incredible person,- self-made in proper American tradition on the one hand, for she had been haunted by the poverty of her childhood, and the years of struggle up from its ugliness,- until she became synonymous with the exotic, exquisite, worshipper at beauty's whrine. Bemelmans draws a portrait in extremes, through apt descriptions, through hilarious anecdote, through surprisingly sympathetic and understanding bits of appreciation. The scene shifts from Hollywood to the home she loved the best in Versailles. One meets in passing a vast roster of famous figures of the international and artistic set. And always one feels Bemelmans, slightly offstage, observing, recording, commenting, illustrated.

Pub Date: Feb. 23, 1955

ISBN: 0670717797

Page Count: -

Publisher: Viking

Review Posted Online: Oct. 25, 2011

Kirkus Reviews Issue: Feb. 1, 1955

More by Ludwig Bemelmans

developed by Ludwig Bemelmans ; illustrated by Steven Salerno

by Ludwig Bemelmans ; illustrated by Steven Salerno

by Ludwig Bemelmans

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The Colossus of New York Paperback – Illustrated, 12 Oct. 2004

Look for Colson Whitehead's new novel, Crook Manifesto !

• Print length 176 pages
• Language English
• Publication date 12 Oct. 2004
• Dimensions 13.21 x 1.27 x 20.32 cm
• ISBN-10 1400031249
• ISBN-13 978-1400031245
• See all details

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Product description

"Impressionistic . . . [an] affecting homage to E.B. White." -- New York Magazine (Top Fall Book Pick)

From the Back Cover

"From theHardcover edition.

About the Author

Product details.

• Publisher ‏ : ‎ Vintage; Illustrated edition (12 Oct. 2004)
• Language ‏ : ‎ English
• Paperback ‏ : ‎ 176 pages
• ISBN-10 ‏ : ‎ 1400031249
• ISBN-13 ‏ : ‎ 978-1400031245
• Dimensions ‏ : ‎ 13.21 x 1.27 x 20.32 cm
• 13,535 in Essays, Journals & Letters
• 14,824 in Travel Writing (Books)
• 137,062 in Literary Fiction (Books)

About the author

Colson whitehead.

Colson Whitehead is the author eight novels and two works on non-fiction, including The Underground Railroad, which received the Pulitzer Prize, the National Book Award, the Carnegie Medal, the Heartland Prize, the Arthur C. Clarke Award, the Hurston-Wright Award, and was longlisted for the Booker Prize. The novel is being adapted by Barry Jenkins into a TV series for Amazon. Whitehead’s The Nickel Boys received the Pulitzer Prize, The Kirkus Prize, and the Orwell Prize for Political Fiction.

A recipient of a Whiting Writers' Award, a Guggenheim Fellowship, and a MacArthur Fellowship, he lives in New York City.

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Review: The Colossus of New York

Dave Film and TV , Reviews

Blu-ray: The Colossus of New York (1958)

Luckily (or not, seeing how the narrative progresses) for him, his father is a brilliant brain surgeon and transplants Jeremey\’s brain into the body of a robotic colossus…that can fire deadly rays from its eyes.

When gaining consciousness, Jeremy fights to keep control over his thought patterns, and only the intervention of his family can stop the impending rampage on the citizens of New York.

I love 50\’s sci-fi movies, and while The Colossus of New York isn\’t up there with the very best of them, it\’s different take on the genre has enough going for it to warrant repeat viewings…especially on this great Blu-ray release from 101 Films.

While the title may well suggest a HUGE creature laying waste to most of the \’Big Apple\’, in reality the \’colossus\’ is no bigger than an average basketball player, and the majority of the \’action\’ takes place in a quaint country estate garden.

Low on action, but high on thought provoking moments, The Colossus of New York poses existential questions about a humans \’soul\’ and if the brain really is the centre of a persons \’being\’.

No flying saucers and no wacky aliens, but more than making up for that with characters that you care about and some genuinely touching moments between a father and his son.

A great commentary with film historians Allan Bryce and Richard Holliss add to the value of an already worthy purchase.

Review by Dave  from a disc kindly supplied by 101 Films .

If you want to buy anything reviewed on our site (or anything at all!), then please use the Amazon link provided and help support us with our website and podcast. Thank you.

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22 details you probably missed in 'Deadpool & Wolverine'

• Ryan Reynolds and Hugh Jackman reprise their Marvel roles for "Deadpool & Wolverine."
• The film includes many callbacks and references to the MCU.
• There are also several cameos that fans might not have noticed.

Warning: Major spoilers ahead for "Deadpool & Wolverine."

Ryan Reynolds has again suited up as Deadpool, and this time he brought Hugh Jackman along for the ride.

Wade Wilson/Deadpool (Reynolds) and Logan/Wolverine (Jackman) team up in " Deadpool & Wolverine ," directed by Shawn Levy.

The film includes subtle callbacks, Easter eggs, and nods to the Marvel Cinematic Universe.

Here's every detail you might have missed.

At his surprise birthday party, Wade tells Buck: "No speaking lines, Buck."

This is a callback to "Deadpool 2," in which Buck (Randal Reeder) goes on a tangent about the Kübler-Ross grief cycle at the bar.

Frustrated, Wade says: "Jesus Christ, Buck. No more speaking lines for you."

Rob McElhenney has a cameo as a TVA soldier.

McElhenney and Reynolds are co-owners of the team Wrexham AFC. McElhenney's "Deadpool & Wolverine" cameo was teased in an episode of their docuseries "Welcome to Wrexham," which was released in May.

Deadpool meets a variant of Wolverine tied to a large X.

This is a reference to the cover art for "Uncanny X-Men" issue No. 251, which depicts a crucified Wolverine.

Deadpool interrupts a fight between Hulk and Wolverine.

This is an obvious nod to their rivalry in the comics. Wolverine makes his debut in issue No. 180 of "The Incredible Hulk."

The brief moment in "Deadpool & Wolverine" also pays homage to the cover art from "The Incredible Hulk" volume one, issue No. 340 by showing Hulk's reflection in the Wolverine variant's claws.

Right before Hulk shoves Deadpool out of the way, the merc says, "I'm Marvel Jesus, you dull creature, and I will not—"

This is a callback to a similar line said by Loki (Tom Hiddleston) in "The Avengers" just before Hulk beat him up. In the movie, Loki says, "I am a god, you dull creature, and I will not be bullied by—."

The Bond-esque Wolverine variant wearing a white suit and eye patch is another nod to the comics.

In the comics, Wolverine dons a similar look and assumes the alias Patch when he goes to Madripoor.

Henry Cavill does the same wind-up motion with his arms from "Mission: Impossible — Fallout."

In "Deadpool & Wolverine," Cavill has a cameo as a Wolverine variant named The Cavillrine. Years earlier, he went viral for reloading his arms during a bathroom fight scene in "Mission: Impossible — Fallout."

Wrexham AFC player Ollie Palmer has a cameo as a bar patron.

Palmer is a striker for the team.

When Wade wakes up in The Void, there's an "Avengers: Secret Wars" comic book on the ground.

This could be a nod to Marvel Studios' upcoming film " Avengers: Secret Wars ," which was announced at San Diego Comic-Con in 2022.

The Void has various remnants of vehicles, monuments, and objects featured in the MCU, including the cupcake delivery truck from the season one premiere of the Disney+ show "Moon Knight."

In "Moon Knight," the pastry truck is part of a high-speed chase sequence.

Bodybuilder Aaron W. Reed, who played Reynolds' jacked body double in "Free Guy," stars as Juggernaut.

Juggernaut is one of the supporting characters that Deadpool and Wolverine encounter in The Void. Reed previously played Reynolds' body double, Dude, in Shawn Levy's 2021 movie "Free Guy."

Deadpool and Wolverine crash into a shop called Liefeld's Just Feet.

This is a nod to Deadpool co-creator Rob Liefeld.

Gordon Reynolds is credited as Nicepool. Gordon is Ryan Reynolds' fake twin brother.

Reynolds plays a Deadpool variant with long hair named Nicepool. In the credits, someone named Gordon Reynolds is listed as playing the character. That's not another Reynolds relative; that's just one of the actor's aliases .

Reynolds previously used the pseudonym Champ Nightingale for double roles in the film " Fast & Furious Presents: Hobbs & Shaw," and to post a fake Amazon review for his gin brand.

Three out of four of Blake and Ryan's kids have cameos.

Reynolds and Lively have four kids : James, Inez, Betty, and Olin. In "Deadpool & Wolverine," James is credited as a screaming mutant. Inez plays Kidpool, and Olin has a cameo as Babypool. Lively also has a role in the film, portraying a female variant of Deadpool named Ladypool .

Betty also gets a shout-out in the credits as "Hugh Jackman Wrangler: Betty Reynolds."

Wrexham AFC player Paul Mullin has a cameo as a variant named Welshpool.

He's one of the 100 Deadpool variants that Deadpool and Wolverine fight late in the movie.

Harry Holland, Tom Holland's younger brother, plays a member of Deadpool Corps.

He's one of the many Deadpool variants in the movie.

Stunt coordinator and second unit director George Cottle revealed Harry's cameo on his Instagram story, posting a photo of Harry unmasked and wearing a Deadpool costume. He's unofficially known as Haroldpool.

The fight with 100 Deadpool variants features a subtle nod to late comic book writer Stan Lee.

Lee made memorable cameos in various Marvel films. Since his death in 2018, Lee has continued to be honored in the MCU.

In "Deadpool & Wolverine," the titular characters fight the variants on a bus, which has a cleaning service ad featuring a photo of Lee.

The movie ends with a callback to "The Avengers."

After saving Deadpool's universe, he suggests getting shawarma with Wolverine.

"I could eat," Wolverine responds.

"Y'know, the Avengers discovered shawarma," Deadpool says, referencing the dish the superheroes ate after the Battle of New York in "The Avengers."

The pizza box at Wade's apartment says Feige's Famous.

This is a nod to Marvel president and "Deadpool & Wolverine" producer Kevin Feige .

The credits include the dedication "For Henry Delaney." Henry is the son of Rob Delaney, who plays Peter.

Henry died in January 2018 at the age of 2 after he was diagnosed with a brain tumor. Rob published a memoir about his son in 2022 titled "A Heart That Works."

There's also a dedication to the late production designer Ray Chan.

Chan died in April at 56 years old. His cause of death wasn't disclosed.

"This film is dedicated to the memory of Raymond Chan," the statement in the film's credits reads. "Ray was our anchor being. His contribution to the film and so many others was a gift which was never taken for granted and will never be forgotten. We'll miss you, Ray."

The credits shout out Len Wein for his "significant contribution to the X-Men."

"Deadpool & Wolverine" credits four people with creating Wolverine: Len Wein, John Romita Sr., Herb Trimpe, and Roy Thomas.

Wein also gets another acknowledgment in the credits, with a line that reads: "The producers would like to recognize Len Wein for his significant contribution to the X-Men."

This might be in response to a controversy that emerged in April, in which Christine Valada , Wein's widow, criticized former Marvel editor in chief Roy Thomas for being credited as a Wolverine co-creator. Typically, comic book writers and artists are given creator credit, not an editor.

Wein, who died in 2017, was best known for co-creating Wolverine and the DC Comics character Swamp Thing. He also co-created the X-Men characters Nightcrawler, Storm, and Colossus.

• Main content

• Entertainment
• Every Cameo in <i>Deadpool & Wolverine</i>

Every Cameo in Deadpool & Wolverine

Warning: This post contains spoilers for Deadool & Wolverine. Hugh Jackman's beloved Wolverine isn't the only mutant to show up in the third Deadpool movie. Deadpool & Wolverine is chock full of superhero cameos from the X-Men universe, Fantastic Four universe, and the Marvel cinematic universe.

How, exactly, all these disparate characters who have never shared a screen before wind up in the same place is rather complicated. As Deadpool (Ryan Reynolds) himself explains in the fourth-wall-breaking movie, Disney merged with 20th Century Fox five years ago. Pre-merger, Disney—who owns Marvel Studios and their MCU—held the rights to the Avengers. Fox, meanwhile, had the rights to the X-Men and Fantastic Four. As of 2019's merger, Disney owns all the characters and has begun to fold the characters of X-Men and Fantastic Four into the MCU.

Deadpool & Wolverine is a love letter to the 20th Century Fox Marvel movies that are largely dead— or getting rebooted —post-merger. Early in the movie, Deadpool and Wolverine get banished to a place called The Void, a kind of dumping ground for comics characters at the end of space and time. There they run into several characters whose own movies were abandoned or never made. Deadpool & Wolverine offers those characters some closure. It even ends with a montage of behind-the-scenes footage from various X-Men and Fantastic Four movies with "Good Riddance" by Green Day, a classic graduation song.

Here are all the cameos you may have missed in Deadpool & Wolverine.

At the beginning of the movie, Deadpool goes universe-hopping to find a Wolverine who can help him save the universe. He encounters several different Logan variants across different timelines, including one who is fighting the Hulk. From the brief glimpse of the big green guy, we'd guess it's Edward Norton from Marvel's 2008 Hulk movie before the role was recast with Mark Ruffalo.

Henry Cavill as Wolverine

In a bit of fan service, Deadpool also runs across a version of Wolverine played by Henry Cavill. Cavill played Superman in the Warner Bros. DC Comics movies, though fans bemoaned the fact that reshoots on Justice League resulted in the post-production team having to digitally remove Cavill's mustache with poor results. Deadpool cracks a joke about how Disney will treat Cavill better than that other studio did.

Chris Evans as The Human Torch

In case you were living under a rock for the 2010s, let me remind you that Chris Evans rose to superstardom playing Captain America in the Avengers movies. Many fans blame the recent MCU slump on the fact that Evans left the franchise after Avengers: Endgame .

So audiences, like Deadpool, were surely elated to see Evans finally return to the MCU. At first, Deadpool and Wolverine hear only his voice, then they see his chiseled jawline. But, in a hilarious twist, when Evans seems poised to utter the iconic phrase, "Avengers, assemble!" he instead calls out, "Flame on!" He catches on fire as he rises into the sky. Unfortunately the bad guys immediately extinguish his flame and he crashes down to earth.

The appearence is another wink at pre-MCU movie history. Before Evans was Captain America he played Johnny Storm, a.k.a. the Human Torch, in the Fantastic Four universe where his power was, well, setting himself on fire.

As he lies smoldering, Wolverine backs away, saying, "We don't know that guy."

"We thought we did," Deadpool adds, a bit depressed.

Toad, Lady Deathstrike, Pryo, Colossus

The villain of the movie, Cassandra Nova, has recruited quite the crew of henchmen from past X-Men films. Among them are Toad (Ray Park) from X-Men , Lady Deathstrike (Kelly Hu) from X-2: X-Men United , Pyro (Aaron Stanford) from X-Men: The Last Stand , and Colossus (Stefan Kapicic) from Deadpool .

Ant-Man's corpse

Does this even really count as a cameo? Nova uses the corpse of a giant version of Ant-Man as her headquarters in The Void. Which Ant-Man, exactly, was sent to The Void and how he died, we do not know. But when Ant-Man's skull is revealed, Deadpool cracks, "Paul Rudd finally aged."

Tyler Mane's Sabretooth

We've gotten two versions of Sabretooth in the Hugh Jackman Wolverine movies. Tyler Mane played the clawed villain in the first X-Men movie where he fought Wolverine on the top of the Statue of Liberty. Ultimately, Sabretooth lost that battle when Cyclops blasted him off the landmark with his laser vision.

Later, Liev Schreiber took over the role in the prequel film X-Men Origins: Wolverine . That film revealed that Sabretooth and Wolverine are half-brothers (though comics readers might take issue with that particular movie invention). But Origins got such bad reviews that most fans pretend it never happened. Indeed, Deadpool himself travels back in time in Deadpool 2 to kill off the version of his character that stars in that film.

Anyway, when Mane's Sabretooth pops up in Deadpool & Wolverine , and Deadpool gleefully tells Wolverine that "people have waited decades for this fight," he's probably referring to the rematch from the original X-Men film.

Jennifer Garner as Elektra

While stuck in the void, Deadpool and Wolverine seek out other superheroes who have been banished to the no man's land. One of the first characters they encounter is Elektra, played by Jennifer Garner in both Daredevil and her solo spinoff film, Elektra .

When she and her friends list off the various superheroes who Cassandra has murdered, they mention that Daredevil died. Longtime Marvel fans may remember that Ben Affleck, Garner's now ex-husband, played that character.

"I'm so sorry," Deadpool says to Elektra of Daredevil's death.

"It's fine," Elektra says in a wink to the audience about the actors' off-screen separation.

Wesley Snipes as Blade

Before there was Iron Man or Spider-Man or even the X-Men on the big screen, there was Blade. The vampire hunter played by Wesley Snipes arguably kicked off the era of modern comic book movies with his 1998 film.

After a long hiatus, Snipes is back. At one point in the film, he quips, "There's only ever been one Blade. There only ever going to be one Blade."

That line seems to be a reference to a cursed reboot of the Blade franchise. A new version of the film starring Oscar-winner Mahershala Ali was announced way back in 2019 but has yet to shoot a single scene. The movie has lost two different directors and reportedly been rewritten several times. When Black Panther director Ryan Coogler recently began production on his own vampire movie starring Michael B. Jordan, fans joked that Coogler was so fed up with the delay he decided to make his own Blade .

Do not fear, Blade fans: Snipes' line seems to be a snarky comment, not a death knell. Marvel Studios head Kevin Feige recently said that the Ali movie is still in the works and teased it will have an R-rating .

Channing Tatum as Gambit

Channing Tatum spent a decade trying to get a Gambit movie made. The actor fell in love with the Cajun thief from the X-Men franchise and co-wrote a screenplay that he's described as an R-rated rom-com. But Gambit got stuck in development hell: Directors like Gore Verbinski ( Pirates of the Caribbean ) and Doug Liman ( Mr. and Mrs. Smith ) came and left the project. Finally, the Disney-Fox merger seemed to kill Tatum's Gambit dreams...until now. Tatum's version of Gambit bemoans the fact that he never got his own movie—his adventures were cut short before they even began.

The version that pops up in Deadpool & Wolverine is admittedly ridiculous. He is incomprehensible. Deadpool pillories Tatum for his poor accent work and frets over the audience missing important exposition. And his ability to make playing cards explode seems silly, until he starts blowing up bad guys.

Dafne Keene as X-23

Deadpool sets the tone for the movie early in its run. In a voiceover says the audience is probably wondering how they will resurrect Hugh Jackman's Wolverine while still respecting his noble death at the end of 2017's Logan . "We're not," Deadpool quips, before exhuming Wolverine's adamantium skeleton and using his bones to brutally murder dozens of enemies.

But one character the movie does respect is X-23. In Logan , the character is played by Dafne Keene, a child who has been experimented on and given Wolverine's DNA. (In the movies, she's basically his clone or his daughter, depending on your perspective.) Wolverine ultimately sacrifices himself to save her.

In Deadpool & Wolverine she shows up largely to buck up Wolverine and tell him he's capable of saving the world, despite his shameful past.

Blake Lively as Lady Deadpool

Ryan Reynolds and Blake Lively are one of Hollywood's most enduring It Couples. They've been spotted hanging out with Taylor Swift backstage at her concerts and traveling to one another's shoots so their family can stay together even as they work on their respective films. So it seemed only a matter of time until Lively cameoed in one of Reynolds' action flicks. She finally does so as Lady Deadpool, the female version of the Merc With a Mouth.

Though we never see Lively's face under the mask, there are several references to Lively throughout the film that hint she might appear. Early in the movie, Deadpool states there are 206 bones in the human body. "207 if I'm watching Gossip Girl ," he gleefully adds, referencing his wife's breakout television series. Later when he's groped during a fight, he yells, "I'm telling Blake!"

And Lady Deadpool herself is previewed by another adoring version of the Deadpool character. "She just had a baby, and you can't even tell," he says, referencing the child that Lively and Reynolds welcomed last year, their fourth. Finally, when Lady Deadpool does show up, she sports a long, high, blonde ponytail, just like the one that Lively herself wore to the premiere of the movie.

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Book Reviews

Blindsided by 'the most': this is a superb novel of a marriage at its breakpoint.

Heller McAlpin

Jessica Anthony's new novel, The Most , blindsided me with its power, much like the cunning tennis strategy from which it gets its title. I don't say this often, but this superb short novel, about a marriage at its breakpoint, deserves to become a classic.

The Most takes place in Newark, Del., over the course of a single, unseasonably warm November day in 1957, which we experience from the two spouses' alternating points of view. We gradually learn a lot about this couple — their aspirations, their personalities, their backgrounds, and the infidelities and secrets they've kept, not altogether successfully, from each other.

Kathleen Lovelace Beckett is a former intercollegiate tennis champion who decided to marry a handsome, easygoing University of Delaware classmate after their graduation in 1948 rather than play professionally. When she wakes up "feeling poorly" one Sunday, nine years into their marriage, she tells her husband, Virgil, to take their two sons to church without her.

After they're gone, Kathleen pulls on her worn red swimsuit from college, pleased that it still fits over her expanded middle, and slips into the kidney-shaped pool in the depressing apartment complex where they've been living "temporarily" for six months and counting after moving back to Delaware from Pawtucket, R.I. Despite her disconcerted husband's repeated pleas during the course of the day as their elderly neighbors look on from their balconies, she refuses to get out. "Geez, Mrs. Beckett," Virgil cajoles Kathleen at one point. "Haven't you cooled off yet?"

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With its echoes of John Cheever's "The Swimmer" and its midcentury details, we're expecting a new take on 20th century suburban malaise. But what we get — along with the green wall-to-wall carpet, the ominous launch of Russia’s Sputnik 2 carrying a doomed "Muttnik" named Laika into space, the '57 Buick Bluebird provided by Virgil's new employer, Equitable Life, against future sales that have not yet materialized — is a story about tradeoffs in marriage and life.

Anthony, who was born in Oneida, N.Y., lives in Maine, where she teaches at Bates College. She is the author of several novels, including the political satire Enter the Aardvark . Among its other merits, The Most offers a lesson in tight construction.

Bridges are a recurrent theme in this story about a married couple suspended over (and sometimes literally immersed in) troubled waters. During the course of this unusual Sunday, Virgil recollects a previously suppressed boyhood memory of seeing a veteran of World War I jump to his death off the newly opened Golden Gate Bridge in 1937. Kathleen recalls the summer of 1942, when her parents ("generous with money if not affection") hired 21-year-old Billy Blasko, a serious Czech-born student, to teach their 16-year-old daughter tennis. Billy's family came from a town "remarkable only for being home to a bridge that had been bombed in the first world war and then had been rebuilt" — before being bombed again during WWII. In 1942, he's living in an area dominated by the wealthy duPonts — which translates as "from the bridges" — while his Jewish family is stuck in Nazi-dominated Europe.

NPR staffers pick their favorite fiction reads of 2024

The son of a famous Czech tennis champion, Billy teaches Kathleen what his father taught him. Tennis, he instructs, is "a kind of dance." Billy drills her in the various moves and the many ways to hit a tennis ball while expanding her worldview by talking to her about what he calls " real subjects," including the war, politics and substantive books. Finally, shortly before their lessons come to an end (for reasons I'll leave to the reader to discover), Billy shares a killer move, meant to be used sparingly. He calls it "the most" — which, he tells Kathleen, translates to "bridge" in Czech. It essentially involves trapping your opponent at the net before letting loose a bomb. A bridge, Billy explains, isn't just a passage, but also a trap.

The strategy lends the novel not just its title, but also a tactic for breaking the impasse in which Kathleen and Virgil and their marriage are stuck. Kathleen, adrift in the pool, intends to blow things up, to detonate the status quo. Her deployment of this stratagem is at once a trap — to force Virgil's hand — and a passage, so they can move on together.

With The Most, Anthony has served an ace.

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After the accidental death of a brilliant scientist his lunatic father and brother transplant the dead mans brain into the body of a giant robot. The operation is successful, but the Colossus Robot mourns for his wife and child and doesn't want to be the guinea pig in his fathers psychotic project and starts displaying homicidal behaviors. Sci-Fi specialist Eughne Lourii (GORGO) directs this FRANKENSTEIN-flavored feature.

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• Release date ‏ : ‎ August 16, 2011
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Behind the malaria vaccines: A 40-year quest against one of humanity’s biggest killers

By Andrew Joseph

Aug. 1, 2024

M alaria is one of our most ancient foes — and one of the wiliest.

Caused by parasites that certain mosquitoes spread through their bites, malaria overwhelms us, establishing an infection before we can put up a fight. It can go on to destroy red blood cells, batter organs, and even damage the brain.

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There are untold millions of cases, the vast majority of them in sub-Saharan Africa. Each year, hundreds of thousands of people die from the condition — some 80% of whom are children under 5. For decades, pharmaceutical companies and academic researchers have struggled to devise vaccines that could confer protection, fueling doubts whether such a product was even possible.

And yet, scientists have now succeeded. Twice over.

Related: 4 takeaways from STAT’s story on the development of malaria vaccines

Earlier this year, routine immunization programs began rolling out a vaccine called RTS,S, reaching children in places including Cameroon, Sierra Leone, and Liberia. Last month, another shot, called R21, was introduced in South Sudan and Côte d’Ivoire, with more countries preparing campaigns for their youngest — and most vulnerable — citizens. RTS,S, also called Mosquirix, was developed by GSK and partners, while scientists at the University of Oxford built R21, which, based on the number of available doses alone, promises to be even more impactful.

Health officials have projected that the shots could save the lives of tens of thousands of kids. In some countries, malaria accounts for 25% of all childhood deaths.

The vaccines — the first to target any human parasite — represent a feat of both scientific grit and fundraising ingenuity. Researchers took on a sophisticated biological adversary that eludes our immune systems’ schemes to identify and dispatch it. They also had to find ways to nudge forward products that would never result in blockbuster sales, a reality that sapped much of the biopharma industry’s interest.

Related: Rollout of a new malaria vaccine kicks off in Africa

“We’re very fortunate, and when I say we I mean our generation, to be present for the last mile of this, and to see these vaccines be introduced,” said Eusebio Macete, a Mozambican researcher who two decades ago helped run an early trial of RTS,S. “And to see that one of the major killers in Africa could now have another tool to save lives, that’s amazing.”

The vaccines are by no means perfect, and given their limited effectiveness and durability, they are not the kinds of interventions expected to eliminate malaria in Africa. Rolling them out also poses huge challenges. The vaccines are given in four doses, starting around 5 months of age and ending over a year later with a booster, at intervals that don’t match when other childhood vaccines are administered. That means health workers must wrangle families to clinics or deliver vaccines to them in some of the globe’s most remote reaches.

The vaccines’ shortcomings have led some experts to argue against spending too much of the world’s resources on them instead of expanding existing measures, like insecticide-treated bed nets, mosquito control, and chemoprevention — that is, giving kids preventative drugs during peak transmission periods. As it is, only some 50% of kids sleep under bed nets in certain areas.

“We believe in the vaccine,” said Scott Filler, the head of malaria at the Global Fund, which helped support RTS,S. But, he said, prioritizing other strategies might offer more bang for the world’s buck. “Maybe we want to spend the world’s money first on these tried-and-true things, lay the foundation, and then start to deploy the vaccine in particular areas that have ongoing transmission, where kids continue to die,” he added.

Other experts are more sanguine, even as they agree that the other interventions need to be maintained. They also argue that now is a particularly important time to take action. Progress against malaria has stalled, and after dropping to 576,000 in 2019, deaths caused by the disease have since surpassed 600,000 a year. Mosquitoes are becoming increasingly resistant to insecticides. The parasite that causes malaria is itself becoming increasingly resistant to medications. Climate change and migrating mosquito species are reshaping transmission zones.

Related: Second-generation mosquito nets prevented 13 million malaria cases in large pilot programs

“We’re at a crossroads,” Mary Hamel, the World Health Organization’s lead for malaria vaccines, told STAT. “We’re seeing cases go up in some places, and we have donors that maybe are not wanting to continue giving as much as they used to give. We’re in a period, I think, that’s precarious.”

This history of the malaria vaccines, an odyssey that stretches across decades and continents, is necessarily an abridged one. But it captures the achievement of how two vaccines reached the finish line within months of each other after more than 40 years of work. It’s one that relied on researchers willing to take on a mission that colleagues saw as quixotic, local investigators who pioneered running trials in their communities, and ultimately, the thousands of parents and children who volunteered for the studies — those who had most closely felt the ravages of malaria and enlisted in the global effort to neutralize one of the leading threats to children.

A sk experts for a good starting point to understand the history of the malaria vaccines, and one name comes up most often: Ruth Nussenzweig. Her work not only demonstrated the theoretical foundation of such a vaccine, but also helped uncover the bullseye that the shots target.

Twice an émigré, Ruth Sonntag was born in Vienna in 1928 into a Jewish family with physician parents. They escaped the Nazi occupation in 1938, eventually settling in Brazil. Her father urged her to become a nurse, thinking she would encounter less antisemitism in that role than as a doctor, but she saw medical school as a path to her real interest: research. It was while she was training at the University of São Paulo that she met another student, Victor Nussenzweig. “I was more interested in doing leftist politics than science, but I started dating Ruth and she convinced me that research would benefit people much more than politics,” Victor once told Science .

By then married, the couple headed to New York University for what they thought would be a brief fellowship for Victor but that turned into an academic home. A 1964 coup in Brazil brought in a period of strict military rule, upending their return.

While in Brazil, the Nussenzweigs had studied a parasitic infection called Chagas disease. By the time she got to NYU, Ruth had her eye on another parasite. Her aim was “always the same thing: develop a vaccine for malaria,” she said in an oral history for the university.

Designing a vaccine is not about attacking a bug directly. It’s about priming a person’s immune system to recognize and fight off a pathogen for itself.

But at the time the Nussenzweigs got to work, it wasn’t clear that that was possible with malaria. After all, there wasn’t a strong natural immune response that a vaccine could replicate. People did accrue some protection to malaria, but only after repeated infections, and it didn’t last all that long. It explained why people could be infected multiple times every year, and while older children and adults might build up enough armor to avoid getting seriously ill, young kids remained vulnerable to severe outcomes.

Nussenzweig, however, doubted the conventional wisdom. “The dogma at the time was that malaria doesn’t induce any immune response,” she said. “This was incorrect, and I knew it.”

She also proved it. In 1967, she and her colleagues showed they could protect mice from malaria by immunizing them with parasites that they had weakened with radiation. These parasites couldn’t cause disease, but they did, Nussenzweig found, elicit an immune response that staved off a future infection. That meant that, maybe, a vaccine could do the same.

Instead of using a whole bug to build a vaccine, which would be far more complicated, scientists often rely on an antigen, or a protein from the pathogen that provokes an immune response. The idea is that those generated immune fighters, namely antibodies, can then swarm invaders when they see the antigen in the form of an actual parasite.

But scientists faced a formidable challenge in identifying a suitable antigen from the malaria parasite, which is a much more complex intruder than the bacteria and viruses other vaccines target. Take the coronavirus that causes Covid-19. It has about a dozen genes, making the virus’s spike protein, which it uses to hack into cells, an obvious antigen to design vaccines around.

The malaria parasite has some 5,000 genes. Not only that, it has infected people for so many generations — our history dates back millions of years, to before we were even Homo sapiens — that it has evolved with us, essentially learning how to throw off our immune system’s defenses.

It gets more dizzying from there. Malaria doesn’t even look the same throughout its time in our bodies. When a female Anopheles mosquito bites us (males are vegetarian), she injects a bit of saliva to ensure the blood doesn’t clot as she takes her meal, which she needs to lay eggs. If she’s infected with the parasites, a few dozen of them will slip with the saliva into our skin. At that point, the parasites are squiggly critters called sporozoites.

Within about 30 minutes, the sporozoites are whisked via the bloodstream to the liver, where they multiply into the thousands over several days before busting out and invading red blood cells, triggering the classic symptoms of fever and chills and causing anemia.

Related: Malaria parasite may trigger human odor to lure mosquitoes

With each infection phase, the parasite shapeshifts, with different genes activated and proteins expressed, becoming almost like a new creature. Any successful vaccine then would not only need the right bullseye, but be able to mount an immune response in the right place in the body, at the right stage of the infection.

Again, Nussenzweig came through. Once her earlier work showed that inducing immunity was possible, her team needed to identify which part of the parasite those elicited antibodies were recognizing — what could be a possible antigen. And together with her husband and other colleagues, she later zeroed in on a protein that surrounded the sporozoite. It became known, in the most scientifically sober way, as the circumsporozoite protein, or CSP. (Other research teams contributed key discoveries around this time.)

That finding became the blueprint for the vaccines. The question was, could you design a shot based on CSP as your antigen, building up an army of anti-CSP antibodies? And could those antibodies then block any injected parasites from making it to the liver, preventing an infection from taking hold?

Ruth Nussenzweig died in 2018 at 89, and Victor, now in his mid-90s, is so hard of hearing that an interview was not feasible, said their son Michel Nussenzweig, himself a scientist at Rockefeller University. But it seemed the couple knew their work might one day result in a breakthrough.

“It is therefore conceivable that a vaccine containing only sporozoite antigens would completely protect a portion of the exposed population,” they wrote in one review .

They authored that paper in 1984. Another 40 years of work remained.

W hen Ripley Ballou’s fever struck, he first thought that he was reacting to the home-brewed beer he had tried at a friend’s party. But as he got sicker, he realized what was actually happening: He had given himself malaria. It also meant his experimental vaccine hadn’t worked.

Ballou, who goes by Rip, was a physician at the Walter Reed Army Institute of Research helping lead a team whose task was to turn the antigen the Nussenzweigs had identified into an actual product. The Army, keen for a vaccine that could protect soldiers, selected a company called Smith, Kline & French as its development partner, striking a collaboration with the GSK precursor in 1984. Their particular target became Plasmodium falciparum — the deadliest form of the malaria parasite, and the one that dominates in sub-Saharan Africa.

When the researchers had their first candidate ready to test, Ballou rallied colleagues to join him in rolling up their sleeves for a challenge study, in which volunteers receive an experimental vaccination, then expose themselves to a pathogen to assess if it worked. (In these tests, the military used a malaria strain they knew was treatable.)

Once Ballou and his comrades got the vaccine, it was mosquito munch time. They pressed gauze-covered cups containing infected mosquitoes against their arms, offering up a blood buffet. Days later, Ballou got sick. So did four others. One person, however, did not .

It was by no means a good result, but it was an important one. “That basically showed us it could be done, that it was possible” for a vaccine to block an infection, Ballou said. But for it to be workable, they would need to show much higher rates of protection.

The team spent the next decade refining the vaccine. There are different ways to present an antigen to the immune system, so they tinkered and toiled in hopes of landing on an approach that could stimulate a response so robust as to be protective. They combined the CSP antigen with genes from other pathogens, and turned to proteins used in other vaccines, and made chains of bits of proteins, all in hopes of whipping up a phalanx of antibodies.

And it just wasn’t working.

“We probably did eight or nine challenge trials where nearly everyone had malaria,” Ballou recalled. They even ran out of friends they could rely on at Walter Reed for the studies, so had to recruit in the local community.

Part of the problem may have been that their experimental vaccines weren’t conjuring up the sky-high antibody levels needed to fend off malaria — much higher than the levels needed to protect against many bacteria and viruses, given that the parasites are so good at evading our defenses.

The antibodies also have to be quite the hunters. To stave off an infection, the immune guardians have to clear out all the injected sporozoites before they make it to the liver. While some scientists say that the more sporozoites that reach the liver, the more likely someone is to get sick, others stress that if even one infiltrates a liver cell and starts replicating, it can turn into a full-blown infection. Imagine a teenager cleaning up from the party he threw with his parents out of town — overlooking even one cup could land him in trouble.

“To say it was a discouraging period does not quite capture the feeling,” Ballou, who is now at the infectious diseases nonprofit IAVI, wrote in 2009 about the failed attempts.

But more than 3,000 miles away, a scientist had an idea.

B efore Joe Cohen became a researcher, his jobs included working in a fabric store’s stockroom and analyzing stool samples at a hospital lab.

Cohen was born in Egypt and, when he moved with his mother to France in 1962 after finishing high school, he halted his studies to support his family. He eventually made it to university, where he focused on agricultural engineering. But really, it was the nascent molecular biology field that caught his eye.

He then joined other relatives who had moved to the United States, but he didn’t know how to apply to doctorate programs. He simply showed up at nearby Brooklyn College one day and introduced himself. He was admitted.

When Cohen was wrapping up his training, he struggled to find an academic job that suited him. But he spotted an ad — he can’t remember if it was in Nature or Science — from Smith, Kline & French in Belgium looking for a molecular biologist with experience in yeast genetics. “That essentially described me,” he said.

It wasn’t academia, but he admired the group’s innovative work on a hepatitis B vaccine in development at the time. So he moved his wife, infant daughter, and aging mutt named Clebs to Belgium in 1984, joining the team right as it was wrapping up its hepatitis B work. It was his first non-trainee job in science, at age 40.

A few years later, Cohen’s bosses asked him to take the lead on the malaria project, which the company was transferring from its U.S. labs to Belgium. Other colleagues had already said no to the assignment, Cohen recalled, thinking it was a lost cause.

Cohen didn’t have much experience with parasites, but the scientific challenge appealed to him. So did the impact he might have if the team succeeded. And in taking on the project, he drew inspiration from the hepatitis B vaccine.

GSK scientists had created that shot by engineering yeast cells to express one of the virus’s proteins, which they had identified could act as an antigen. When researchers would crack open the cells, the proteins would spontaneously glom onto each other, forming what’s called a virus-like particle. The vaccine was made of schools of those particles.

What if, Cohen thought, you could just add CSP — the malaria antigen — into the mix?

Cohen grinded away in the lab, into the night, on weekends, on holidays. By linking genes from the hepatitis B virus and the malaria parasite, he was able to express what are known as fusion proteins in the yeast cells — meaning they had antigens from both pathogens — that he still got to ball together into virus-like particles. They looked like blobs encircled by a coating of hepatitis B antigens, and then, jutting out from the surface, like cloves studding an orange, were the malaria antigens.

Related: WHO recommends second malaria vaccine, hoping to address supply issues

The theory was that by presenting the body with a virus-like particle — which resembled a virus in both size and shape — the immune system was going to generate a heartier response than it would when presented with just a bit of the protein itself. After all, the immune system knows what to do when it sees something that looks like a virus.

As it happened, other GSK scientists were building up another branch of vaccine research. They were designing a line of adjuvants, which boost the power of a vaccine by deepening the immune response. Researchers started testing the malaria shot in combination with a number of the adjuvants.

Then, finally, came the challenge study of the vaccine with an adjuvant called AS02.

Ballou was in his kitchen when he got the call: Six of seven volunteers had been protected , as the scientists reported in the New England Journal of Medicine in early 1997.

The vaccine, dubbed RTS,S, had worked. It was time to test it in the field.

O ne of the team’s early calls was to a researcher named Brian Greenwood. Greenwood had already proven the power of insecticide-treated bed nets, but he believed in vaccines, even as other experts dismissed them. Greenwood once even made a bet with another senior scientist — whom he declined to name — about whether the world would ever see a malaria vaccine.

Greenwood, who is British, was running a research site in the Gambia. He had previously worked on a study in Tanzania of a vaccine candidate developed by a Colombian scientist named Manuel Patarroyo, and while that shot ultimately fizzled out, the experience left Greenwood with a lesson. “It taught us how to do a malaria vaccine trial,” he said.

Greenwood and colleagues started recruiting a cohort of men to evaluate RTS,S, with some receiving the experimental shot and some getting a rabies vaccine as the control. At the time, the researchers thought a highly effective vaccine could still be used for adults. Plus, it’s considered unethical to test a vaccine in children before its safety is established in older volunteers.

The results , published in 2001, were a bit of a bust. The shots showed some protection, but it wasn’t very strong and waned quickly. As Ballou wrote in a review , “the vaccine was still clearly not sufficiently efficacious to support its further development as a stand-alone vaccine for travelers or the military.”

But the adult trial furthered the researchers’ belief that the shot had pediatric potential. They reasoned that if the vaccine reduced the risk of malaria to an extent in adults, it was likely to be even more protective in kids, who tend to mount stronger immune responses to vaccines.

The prospect of healthy returns had evaporated, however. A company could never charge much for a product whose only takers would be children in some of the world’s poorest countries. Wealthy tourists and the Defense Department they were not.

Related: GSK CEO on pharma giant’s new direction: ‘We’re in the business of preventing and treating disease’

GSK brass allowed the team to continue with the program, but there was a catch: The company would no longer fund the project without others’ support.

It was a key inflection point, one that underscores how commercial realities shape the programs drugmakers pursue or scuttle. It’s not just the programs companies back, either. With potentially lucrative products, companies start planning future trials and scaling manufacturing at risk even before the prior step in the development gauntlet is complete, all to expedite the process. With neglected disease products, it’s likely that no one is going to put up the money for the next study until it’s clear that it’s going to happen, a factor that dragged out the timeframe of the malaria vaccines.

Public health experts credit GSK for sticking with the malaria program at all, particularly given its daunting nature, and say it’s unclear whether other companies would have done the same. Thomas Breuer, GSK’s chief global health officer, said in an interview with STAT that the company has covered the “lion’s share” of funding for RTS,S throughout its development, at more than $700 million.

While GSK has faced recent criticism for how it’s handled the development of a tuberculosis vaccine , Breuer said that the drugmaker sees a need to partner on these products, not just to share the financial risk, but because the company doesn’t have all the relevant expertise itself. He stressed that GSK continues to invest in global health.

“We have a social responsibility, and this was not just true for the malaria vaccine,” he said, citing the company’s development work in other neglected diseases. But, he added, “Even GSK, who is committed in the long run, cannot fund all the activities.”

Luckily, another funding model was emerging around that time. The Bill & Melinda Gates Foundation, established in 2000, had started backing a nonprofit called PATH and its Malaria Vaccine Initiative. And in 2001, GSK and PATH struck a partnership to push RTS,S forward. In total, said Helen Jamet, a malaria official at the Gates Foundation, the organization put $200 million into RTS,S, primarily through PATH’s work.

With that partnership in place, researchers moved to test the vaccine in kids. For the site, they selected Centro de Investigação em Saúde in Manhiça, Mozambique, which Spanish experts had helped start, but, crucially, was staffed largely by local providers. The team set out to recruit parents in the community to enroll their children in the study, setting aside time to talk with them about the vaccine and address their questions.

It helped that parents were well aware of the risks posed by malaria. Children would get sick two, five, eight times a year. Kids would miss school, and parents would miss work to care for them. At hospitals, where even now a third of consultations in some regions are tied to malaria, bags of blood being readied for transfusions would line the walls. Clinics would be so full that three children would share a bed, all pale and flopped over and breathing shallowly.

Laurinda Carlos Balate was one of the moms who said yes to the study. Some of her friends didn’t understand why, and told her the experimental shot might be dangerous. But she liked the idea of combating malaria, and she trusted the clinic’s staff.

“I’m quite happy, because the vaccine was a success,” she said recently over Zoom.

Her daughter, Loyde Carina Nhabanga, who was just a baby when her mother enrolled her in the study, now has a 7-month-old of her own, whom she said she is planning on getting vaccinated when the shots become available. “It’s going to help us fight against malaria,” she said.

Overall, the Phase 2 trial, run in 2,000 children, showed the vaccine was 30% effective at preventing malaria, and 58% effective at protecting against severe malaria, according to findings published in 2004. It was the first sign that the vaccine could generate a protective response in kids in high-transmission areas.

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Other studies of RTS,S showed similar outcomes, building evidence that was promising enough to move the shot into a pivotal Phase 3 trial. (During this series of trials, the researchers switched the adjuvant from AS02 to one called AS01 that prompted stronger immune responses. AS01 is also used in GSK’s RSV and shingles vaccines.)

It was around this time that researchers in England came up with their own vaccine candidate.

A drian Hill came to malaria vaccines through a circuitous route. Hill, now the director of the University of Oxford’s Jenner Institute, had trained as a geneticist, studying how different genetic variants that had evolved in certain communities made people less vulnerable to malaria. (If the legacy of malaria is written in our history books — it may have killed Alexander the Great, Genghis Khan, and a couple of popes — it is also imprinted in our DNA.)

It was when Hill was studying one of those variants in the Gambia in the 1980s that he got an up-close look at the parasite’s toll. Children were packed into a clinic, arriving so sick they desperately needed blood transfusions. So he pivoted.

“That kind of converted me from thinking, we’ve got to really understand susceptibility to malaria, to thinking, what’s going on with vaccines?” he said in an interview at his Oxford office.

Starting in the 1990s, Hill and his colleagues threw a number of strategies at malaria. They tried DNA-based vaccines and viral vector vaccines — like the one Oxford researchers would later develop with AstraZeneca against Covid-19 — and different combinations of those different kinds of vaccines, without much success.

But they also thought of updating RTS,S. After all, by the early 2010s, some two decades of advances in research methods — including in expressing proteins in yeast — had accrued since the early days of the GSK shot. “Making the vaccine 25 years later helped us,” Hill said.

The issue with RTS,S, at least as far as Hill and his colleagues believed, was that there wasn’t enough malaria antigen on the particle versus hepatitis B antigen. They hypothesized that if they could engineer both a greater amount and higher density of the former, the particle would elicit a more powerful anti-malaria immune response, with more antibodies produced that were even sharper at targeting sporozoites. They essentially wanted to stud more cloves onto the orange.

The task of figuring it out fell to a graduate student named Katharine Collins. The potential trip-up was that if the Oxford researchers increased the amount of malaria antigen in their recipe, the proteins wouldn’t self-assemble into a virus-like particle, which was crucial to generating an actionable immune response. Whether or not proteins arrange into that kind of particle depends on a delicate balance of chemical charges, with the right bonds needed to form for it to be a stable molecule.

It took some trial and error, but by refining the process, Collins made it happen. “I would express the protein in the yeast, bust them open, do a really simple purification, and then go and have a look under an electron microscope,” said Collins, who now works at the charity Open Philanthropy. “And we saw particles. It was like, ‘wow.’”

For their adjuvant, the Oxford team landed on one called Matrix-M from Novavax, which is now used in that company’s Covid jab. The shot became known as R21.

But like RTS,S, R21 ran into funding issues. When it came time to manufacture doses for human trials, Hill turned to Oxford’s own production site, which was cheaper than a contract manufacturer. But with limited resources and know-how, the team struggled to make the vaccine at scale. From the promising lab experiments to having doses for a challenge trial, three years would pass.

W hen data from the Phase 3 trial of RTS,S arrived , the reaction was lukewarm.

The trial, which ran from 2009 to 2014, enrolled nearly 9,000 children from 5 months to 17 months of age in seven countries, places where malaria circulated year-round as well as places with seasonal transmission. While the initial protection appeared strong, the efficacy dropped to between 30% and 50%. Adjectives like “modest” and “moderate” were thrown around.

Some experts excavated a rosier view. Given the scope of the disease, they argued, preventing even a third of malaria cases would have major repercussions for health systems, economies, and families.

“Because of the sheer number of cases of malaria — there are hundreds of millions of cases of malaria every year — what we saw was that in some of the areas where the intensity of malaria transmission was higher, where children got more malaria, we saw over 6,000 cases of malaria prevented for every thousand children vaccinated,” said Ashley Birkett, a longtime PATH official.

But another issue arose — potential safety signals with the vaccine. One was that there were more cases of meningitis, an inflammation around the brain and spinal cord, among children who received RTS,S than those who got the control shots.

It was up to regulators to weigh in. The European Medicines Agency gave the vaccine a positive review in 2015, but it was a WHO recommendation that mattered most. The global agency needs to give its stamp of approval if groups like UNICEF and Gavi, an international organization known as the Vaccine Alliance, which help purchase immunizations and deliver them to low-income countries, are going to add a shot to the portfolio of products they provide.

The WHO’s advisers weren’t overly enthusiastic. Based on the data, the vaccine didn’t seem like a game-changing intervention. With the potential safety issue, they worried not only that introducing the vaccine might lead to meningitis cases, but that moving too quickly could turn people against other immunizations.

The context of the moment also shaped experts’ thinking, those involved at the time recalled in recent interviews. The world had been making steady progress against malaria, with cases cut by 27% from 2000 to 2015. No one foresaw that tide reversing.

“There was not a sense that we desperately needed a vaccine, let alone a vaccine with modest efficacy,” said Pedro Alonso, who directed WHO’s malaria program at the time.

Related: The WHO’s chief scientist on Covid-19 vaccines, patent battles, and speeding up access in Africa

Instead of recommending the vaccine, the WHO in 2016 decided to push forward with a pilot program, which would involve deploying millions of doses to children in three countries. The move was seen as a compromise — the agency was not spurning the vaccine, but it wasn’t endorsing its wide rollout either. The program would also provide the chance for experts to assess the feasibility of using the vaccine outside a trial. Would people get their children to a clinic for four doses? Would they give up other safeguards against malaria?

But if the pilot made sense as a way of shoring up the vaccine’s evidence, it created a new challenge, one that some experts worried could jeopardize the shot. As Birkett said, “Nobody was anticipating the pilot program. Nobody had the money ready to go.”

The Gates Foundation by that point had pulled back from putting more funding into RTS,S, but the WHO scrounged $70 million for the pilot from sources including Unitaid, Gavi, and the Global Fund, with doses donated by GSK. But the time needed to fundraise and plan, including getting the three selected countries — Ghana, Malawi, and Kenya — on board, meant shots didn’t start being administered until 2019, three years after the pilot was decided on.

Once underway, it became clear that the meningitis issue was a statistical fluke from the trial — that there was no real safety issue. And in 2021, the WHO endorsed RTS,S as the world’s first malaria vaccine .

Ultimately, the pilot program demonstrated not only that RTS,S could be reliably rolled out, but that even with its modest efficacy, it could have sweeping impacts. It didn’t lead to drops in other vaccinations. Families kept up with other anti-malaria interventions. And it cut childhood mortality broadly by more than 10%, a sign, perhaps, of how malaria infections leave children vulnerable to other illnesses. Places where the shots were deployed saw malaria hospitalizations cut by a fifth.

“These numbers are huge,” said Kwaku Poku Asante, the director of Ghana’s Kintampo Health Research Centre and an investigator in the pilot program. “If you sit in a district hospital, where every child has malaria, and all of a sudden you’re seeing a reduction by one-fifth, that is huge.”

Some experts maintain the pilot program was necessary — that a wide-scale rollout would not have succeeded had WHO recommended RTS,S in 2016. But in hindsight, others are more conflicted. They find themselves wrestling with the decision, wondering if the vaccine had been put into use then, instead of years later, how many more thousands of children might have been saved?

“This has haunted me for a number of years. The question is, did we do the right thing, or did we not?” said Alonso, now at the University of Barcelona. “I do often think of the costs.”

A fter a successful challenge trial and safety tests, it was time for the Oxford team to try R21 in the field. They scraped together funding from sources including the Wellcome Trust and the European and Developing Countries Clinical Trials Partnership, and in 2019 launched a Phase 2 trial in children from 5 months to 17 months of age in Nanoro, Burkina Faso.

The results surpassed their hopes. The shot showed about 75% efficacy.

“We were expecting in the best case scenario 60% efficacy or something like that,” said Halidou Tinto, who leads the clinical research unit in Nanoro. “And then we were at almost 80%. This was a big surprise, but a very nice surprise.”

For the Phase 3 study, instead of the Oxford team having to pitch companies to fund the research, a partner came to them. One day in 2017, a man named Umesh Shaligram showed up at Hill’s office. Shaligram was a top scientist at the Serum Institute of India, the world’s largest vaccine manufacturer. The institute had heard about Oxford’s promising data, he told Hill, and was curious to learn more.

With the resulting pact between Oxford and Serum, not only did Serum start manufacturing R21, it even funded the Phase 3 trial, a study of 5,000 children in four countries run in 2021 and 2022. The vaccine showed about 70% efficacy.

Last October, the WHO recommended the vaccine .

A few months ago, a package arrived for Brian Greenwood, the old malaria hand who had helped run the early RTS,S trial in the Gambia. It contained six “very nice” bottles of red wine. The other expert with whom Greenwood had made a bet about the feasibility of a malaria vaccine was making good after losing that decades-old wager.

The bottles’ arrival coincided with the rollout of RTS,S in Cameroon in January, the first time a malaria shot was deployed in a routine immunization program. More countries will launch their own vaccination campaigns in the coming months.

Experts debate whether one vaccine is superior to the other. Many favor R21, pointing to its updated design and the higher efficacy scores it reached in trials. Others counter that the differences in the trials — including the timing of the doses relative to peak transmission periods — render comparisons impossible. The WHO has taken to saying that both shots can reduce malaria cases by about 75% when given before peak transmission periods and combined with other interventions.

“The important thing now is to get the vaccines used,” said Greenwood, who worked on studies of both shots and is now at the London School of Hygiene & Tropical Medicine.

R21 does have some inarguable advantages. While manufacturing is still being scaled up , thanks to the partnership with the Serum Institute, 100 million doses could be produced a year, at a cost of $2 to $4 per dose. GSK, meanwhile, is only producing 18 million RTS,S doses from 2023 to 2025, at an approximate cost of $10 per dose, and then committing 15 million doses a year from 2026 to 2028. The company is transferring the vaccine to Bharat Biotech, another large Indian manufacturer, which should result in more doses at a lower cost, but it’s expected that the Bharat facility won’t be supplying RTS,S until 2028.

The vaccines are important in other ways. They established how to run clinical studies, built up trial infrastructures, and gave regulators experience evaluating malaria shots. Even with the financial challenges it faced, R21, with its strong data profile, comparatively breezed through its studies and regulatory reviews, winning approval faster than many experts anticipated. Future vaccines could have an even more streamlined route.

And next-generation vaccines are coming. Some target different life stages of the parasite, so could be combined with a shot like R21. Some could protect adults — including, crucially, during pregnancy, a time when a malaria infection is dangerous to both mother and baby. They could have higher efficacy, greater durability, and even halt transmission — the type of tool that could make eradication a prospect.

In that way, then, RTS,S and R21 have another legacy. They showed that a malaria vaccine was possible.

About the Author

Andrew joseph.

Europe Correspondent

Andrew Joseph covers health, medicine, and the biopharma industry in Europe.

children's health

global health

public health

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