Patrick Soon-Shiong hopes an experimental COVID-19 vaccine from his companies will prove its worth in monkeys.

David Paul Morris/Bloomberg via Getty Images

Sciences COVID-19 reporting is supported by the Pulitzer Center.

The race for a COVID-19 vaccine has a dark horse entrant. Billionaire scientist and businessman Patrick Soon-Shiong announced in a 27 May investor call and press release that an experimental vaccine being developed by two of his companies is on the short list of 14 candidates being evaluated by Operation Warp Speed, the Trump administration’s push to deliver 300 million doses of safe and effective COVID-19 vaccines by January 2021.

Although the Department of Health and Human Services (HHS) has so far announced financial backing for five other vaccine candidates, including from Moderna, Johnson & Johnson, and AstraZeneca, it has not publicly said a word about Soon-Shiong’s vaccine. Nor has HHS committed any money to the effort so far, Soon-Shiong acknowledges, although he says Warp Speed is arranging monkey tests of the vaccine by a federal lab. “We’re not confirming anyone’s involvement in the initial group [of vaccines] unless a company is bound by fiduciary requirements to report contractual agreements,” says Michael Caputo, an HHS spokesperson for Warp Speed.

Soon-Shiong’s companies, the publicly traded NantKwest and the privately held ImmunityBio, have not published any data on their vaccine, which takes an unusual approach to stimulating an immune response against SARS-CoV-2, the virus that causes COVID-19. According to a 27 May version of a COVID-19 vaccine table regularly updated by the World Health Organization (WHO), 125 candidates are in development—and the NantKwest/ImmunityBio candidate is not among them. “We’ve been stealth,” Soon-Shiong says, explaining that until the investor call he tried to avoid attention for the vaccine candidate because of widespread assertions that he oversells his projects.

Soon-Shiong says after he and his team made a Zoom presentation to HHS on 9 April, they were invited to submit a full proposal and told that their vaccine would be among the candidates that Warp Speed assesses in head-to-head monkey studies. Soon-Shiong says he likes the idea of taking part in a careful comparison, and he also wants the government’s support to help produce what he projects could be more than 1 billion doses of the vaccine by the end of 2021.

Soon-Shiong, owner of The Los Angeles Times newspaper and a part owner of the Los Angeles Lakers basketball team, has drawn extensive media coverage for his ambitious goals, such as wanting to “create a revolution” in cancer treatment through NantWorks, the umbrella of NantKwest and eight other companies. But he has also received sharp criticisms—including in STAT and Forbes—for not delivering on those promises and repackaging what others see as conventional wisdom. His COVID-19 vaccine project does, however, have unique features.

The spike surface protein of SARS-CoV-2, the cause of COVID-19, typically forms trimers in which each spike’s tip—the key to binding to human cells—is either in an “up” (cyan) or “down” (magenta and pink) position, a variable that could influence the strength of the antibody response to a vaccine using the protein.

Nicholas Wu/Wilson lab/Scripps Research

As with three other candidates on the WHO list, the NantKwest/ImmunityBio vaccine uses an adenovirus designated Ad5—one of a large family of viruses that cause some common colds—engineered to hold a gene for “spike,” the surface protein of SARS-CoV-2. This engineered Ad5 aims to infect cells, shuttling the spike gene into them. When the cells manufacture spike, it should trigger the production of antibodies against the virus and potentially other protective immune responses.

A drawback of Ad5 as a vaccine vector is that the virus has already spread widely through many populations. If people have preexisting Ad5 immunity, it can knock out the vector before it has a chance to infect cells and produce SARS-CoV-2 proteins. To counter that problem, an ImmunityBio subsidiary modified Ad5 by deleting several of its genes in an attempt to make it less visible to the immune system.

In another novel feature, Soon-Shiong’s group uses this altered Ad5 to deliver a second SARS-CoV-2 gene, for the nucleocapsid protein the virus uses to package its RNA. The researchers hope the nucleocapsid protein will boost what are known as T helper cells, which can supercharge the B cells that make antibodies.

Soon-Shiong contends that the second protein also strengthens the immune response to the key part of spike: the receptor-binding domain (RBD) that initiates the infection of human cells.

In SARS-CoV-2 and other coronaviruses, spike studs the surface of the virus in three-leaf clovers of sorts called trimers. Structural biologists have shown these trimers typically have two RBDs facing down and only one turned up, making it most visible to the immune system. Soon-Shiong says the nucleocapsid in the vaccine preparation somehow interacts with spike and “pushes RBD out and probably exposes the downs into more up positions.” Data from preliminary studies in test tubes and mice, which Soon-Shiong shared at the investor meeting, suggest the strategy elicits a stronger immune response, he says.

Florian Krammer, whose lab at the Icahn School of Medicine at Mount Sinai studies different COVID-19 vaccines in mice, says “adding the nucleocapsid is probably not a bad idea,” but he notes that spike itself can stimulate T cells. He also says three upfacing RBDs may be overkill. “I’m not sure if the up confirmation is making a huge difference,” Krammer says.

Andrew Ward, a structural biologist at Scripps Research whose lab has helped characterize spike on several coronaviruses, also questions whether RBDs in actual viruses really are arranged in the one up-two down configuration. The idea may reflect sampling bias, he says. Structural biologists select from a population of spike proteins in a solution, and one up-two down are the easiest ones for them to characterize. “You’re selecting for things that are most well behaved,” Ward says. “People are taking a huge leap from those structures.”

Some researchers also worry about the Ad5 vector itself because of bad results in a 2007 trial of an HIV vaccine made with the vector, in which more vaccinated people became infected than those who received a placebo shot. Many immunologists suspect the Ad5 led to an especially large increase in CD4 T cells, the favorite target of HIV. Conceivably, any COVID-19 vaccine that uses the Ad5 vector could increase the risk of HIV infection. Soon-Shiong says his vaccine’s modified Ad5 won’t cause this problem, although his companies have yet to publish evidence to support that.

Soon-Shiong says his companies signed an agreement with HHS on Friday for the monkey study’s protocol and hope to receive approval from the Food and Drug Administration to begin an initial safety trial in humans in June. Warp Speed has said it plans to whittle down the 14 candidates from its initial selection to about eight for early stage human trials. “We will inform the public very soon about the candidates that make the first cut,” Caputo says. Although Soon-Shiong hopes to win the substantial backing the government has provided to other vaccinemakers, he assures that, whatever happens, his companies will continue to pursue the project “with gusto.”

source: sciencemag.org

LEAVE A REPLY

Please enter your comment!
Please enter your name here