“Vaccines, obviously, are the ultimate solution for pandemics,” Rino Rappuoli told BioWorld. They have, he added, “already eliminated a lot of pandemic threats – smallpox, influenza, poliomyelitis.”

And the road to normalcy from the current pandemic, or any pandemic, is likely to be open only once there is a vaccine. A pandemic vaccine, by its nature, cannot be developed in advance. But technology could make vaccines available more quickly, at least in future pandemics.

Like the mRNA-based antibodies that can potentially shave months or years off the development of antibody treatments, nucleic acid-based vaccines are faster to make than traditional vaccines, which administer the antigen as a protein.

The first patient in an NIH-led trial was dosed with mRNA-based SARS-CoV-2 vaccine mRNA-1273 (Moderna Therapeutics Inc.) in mid-March. Moderna also has the Zika vaccine mRNA-1893, the influenza H7N9 vaccine mRNA-1851 and the anti-Chikungunya antibody mRNA-1944 in phase I.

A second, DNA-based vaccine, INO-4800 (Inovio Pharmaceuticals Inc.), began dosing volunteers in the first week of April. Inovio vaccines are in clinical trials for HIV, Ebola, Zika, Lassa fever, MERS and now COVID-19.

Nucleic acid-based vaccines can be developed extremely rapidly compared to protein-based vaccines.

Rino Rappuoli, chief scientist, GSK Vaccines

But Rappuoli, chief scientist at the GSK Vaccines arm of Glaxosmithkline plc, predicted that protein-based vaccines will end up providing the bulk of vaccine.

Nucleic acid vaccines are “faster in the beginning. They will be the first ones to get into efficacy clinical trials,” he said.

But protein-based vaccines, in his opinion, will pull ahead during scale-up. “The ones that are well-established, we are experienced with them, and there is experience on manufacturing,” he said. “If we are going to need hundreds of millions of doses, that is the only platform that can make those doses available.”

He stressed that his prediction is “specific for this situation,” and that the COVID-19 pandemic could be the opportunity to test RNA-based vaccines.

Rappuoli is not clinging to the old ways on principle – he and his colleagues developed the first mRNA-based vaccine, against the potential pandemic influenza strain H7N9.

When that virus was first identified as a novel influenza strain in 2013, the Chinese Center for Disease Control and Prevention published the gene sequence of its hemagglutinin and neuraminidase.

The scientists were able to produce RNA for the protein using the published sequences, a feat that Rappuoli described in a presentation at the International Conference on Antimicrobials and Chemotherapy and the International Congress of Chemotherapy (ICAAC/ICC) 2015 annual meeting as "basically teleporting the organism."

"We had a vaccine before the wild-type virus had reached the CDC," Rappuoli said in 2015. "This gives you an idea of what kind of game-changer this could be."

The fact that a potential game-changer developed in 2013 is not ready for prime time for a 2020 pandemic illustrates an inconvenient truth: that a significant part of the COVID-19 disaster is due to a failure to prepare.

“Our society has been reasonably good in investment for car accidents, [for example,] seat belts,” he said. “Remarkably, when it comes to health, we have not been able to make that kind of investment.

“We could be much better prepared – with vaccines, with diagnostics, even with human monoclonal antibodies,” Rappuoli said. “All the technologies are available but, obviously, there is no market. That is really the problem that we have: Create a sustainable market for things that we hope will never come.”

Nice vax if you can get it: Stretching vaccine supply

Once there is a licensed vaccine, producing enough doses to cover the global population will be the major order of the day.

One way to stretch the supply is to improve delivery.

There are multiple technologies in development to deliver vaccines to the skin rather than muscles.

At least one research group has used a tattoo gun to deliver DNA to the skin, while Inovio’s Cellectra device uses electroporation to briefly open cell membranes and allow the intradermal delivery of INO-4800.

In a study published in the April 1, 2020, online issue of Ebiomedicine, researchers at the University of Pittsburgh Medical Center reported using a microneedle device that was made up of antigen and sugar, and dissolved into the skin upon administration.

The study described in Ebiomedicine began prior to the advent of SARs-CoV-2, and so the bulk of the work was done on MERS-CoV. Using MERS-CoV antigen, the team showed that, in mice, they could induce a yearlong antibody response with a MERS-CoV antigen and a TLR agonist. The team also demonstrated that the initial response to SARS-CoV-2 was similar to the MERS-CoV response.

David Hoey, CEO of Australian company Vaxxas Pty Ltd., said it is not surprising that the delivery to the skin will give a stronger immune response than the usual intramuscular jab.

The skin is the body’s largest immune organ, and any injury to the skin will set off an immediate influx of immune cells.

“The dendritic cells are just sitting there, waiting,” he said. “If you go into your garden and get a little scratch – within seconds, you’ve got that redness that is a sign of almost immediate inflammatory response.”

Any antigen will be picked up by those dendritic cells and delivered to the lymph nodes. In the muscle, Hoey said, that antigen basically “has to wander around to bump into an immune cell.”

The reason that micropatches have not replaced the standard intramuscular vaccine, he said, is that “so far, needles are cheapest… At the end of the day, the patches are much more complicated. And you need to be able to make them by the tens of millions to get the economics right.”

Vaxxas, he said, “has focused every aspect of the device on making it workable at scale.”

Credit: Centers for Disease Control and Prevention

The company recently reported results from a phase I influenza vaccination trial using its high-density microarray patch (HD-MAP). Hoey said it was the largest trial to date using micropatch technology to deliver vaccines.

In that trial, the authors showed that compared to intramuscular delivery, a sixfold smaller dose of influenza vaccine delivered by HD-MAP led to an equivalent immune response as measured by hemagglutinin inhibition and microneutralization.

Hoey pointed out that in a pandemic situation in particular, intradermal delivery could have another advantage as well.

If it is sufficiently simple, it could be self-administered at home, “instead of having the entire population congregate at a single point to be vaccinated, which is the exact thing you’re trying to avoid” in a pandemic scenario, he said.

While home administration of childhood vaccines is unlikely to become standard because of the potential high cost of an error, even for seasonal flu, “if the population [self-vaccinated], and they didn’t do it perfectly, but they did it every year, it would almost make sense to have a subscription model.

And in the case of a pandemic, he said, “the rules get changed. If it costs the economy $5 trillion over six months, then self-administration looks like a no brainer if you have a vaccine that works.”

The device itself can also be produced in advanced and stockpiled to be combined with the vaccine for whatever turns out to be the next emerging epidemic or pandemic.

And because the vaccine material is dry, it can be stored at high temperatures – Vaxxas has demonstrated stability for a year at 40 degrees Celsius – simplifying the logistics of storage and transportation.

“Any vaccine that we take, we have to change it to make sure that it’s stable when it’s dry,” Hoey said, which does take some additional time.

But once that formulation is successful, “in the context of a pandemic, you’re able to do things that simply can’t be done with a needle and syringe.”

And “we’ve done work with DNA, we’ve done work with RNA, conjugates, with and without adjuvants – there isn’t a vaccine construct we’ve found that doesn’t work, nor a disease that acts differently.”

Speaking of adjuvants

Adjuvants boost the immune response to infections. Like intradermal vaccination itself, they reduce the dose of vaccine necessary to get a protective immune response.

In a 2018 paper published in Science Advances, researchers from the Infectious Disease Research Institute (IDRI) and colleagues reported preclinical results of the first adjuvanted intradermal vaccination, against the H5N1 avian influenza strain noted for its 60% lethality rate in humans. In ferrets, the adjuvanted vaccine induced protection with a single dose, while in a phase I trial, immune responses were “above approvable endpoints for a protective flu vaccine,” the authors wrote.

IDRI is testing a number of different adjuvants. Furthest along, in phase II trials, is GLA-SE, a TLR agonist related to GLA-AF, which is in phase I.

A 2012 paper demonstrated that in preclinical experiments, GLA-SE reduced the amount of recombinant H5N1 flu antigen to 1/30th of the dose that was necessary without an adjuvant.

Furthermore, IDRI CEO Corey Casper told BioWorld, “when you give just the adjuvant alone, you can protect… against a challenge with pandemic influenza,” making adjuvants another potential stopgap in a pandemic situation.

Universal vaccines against viral families

Even though it is impossible to develop vaccines against an unknown future disease, it may be possible to create broad-spectrum vaccines to viral families.

Even a universal vaccine might need to be administered annually, as its protection might not be long-lasting. How long infected and recovered individuals will remain protected from SARS-CoV-2 is one of the critical unanswered questions of the current pandemic, and a vaccine will be no different. But it would be effective regardless of strain.

Such a universal vaccine has been a longstanding goal for influenza. Two such universal vaccines are currently in phase II testing.

The NIAID is testing M-001 by Biondvax Pharmaceuticals Inc., which consists of multiple antigens from different flu strains.

Flu-V, which in March reported success at preventing mild to moderate influenza disease in a phase IIb trial, is a peptide vaccine derived from conserved regions of internal viral proteins that aims to provide protection via a T-cell response.

The principle of developing broad-spectrum vaccines via one or more of those approaches is applicable to other viral families, including coronavirus, GSK’s Rappuoli said. “I think it is possible, with the technologies we have today, to develop vaccines that would cover more than one coronavirus.”

Editor’s note: Today’s story is the fourth and final story in “The next pandemic” series. Read part 1 focusing on surveillance for the next pandemic, part 2 focusing on diagnostics and part 3 focusing on drug development. BioWorld also has been tracking drugs and vaccines in development for COVID-19.

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