Fig. 1|Comparison ofselected indevelopment against COVID-19. a government agencies such as Food the and Administration Drug of experience previous USA,the the outbreaks viral prepared two things together gave alot of insight.” mechanisms by can enter which viruses cells,” he said. “Those that by recognized can be neutralizing antibodies, and the our understanding about determinants the both of spikes viral sible before. For example, an really has “There explosion been in for rational the designof vaccines inaway that was never pos- and human immunology over past the few decades has allowed According to Nabel, improved understanding of viruses both than as adecade head of the Research Center at NIAID. Sanofi, where CSOsince 2012,following he had been more Therapeutics. Nabel cofounded ModeX in2020after leaving and CEOof multispecific immunotherapy company ModeX and novel platforms, technology Nabel, says Gary President rests on government and investments industry in basic research to prepare for future. the evaluated But in clinical trials. it laid bare also work the to left do rapidlycould be applied to respond to threat the had already been pandemic was fortuitous, in that novel vaccine technologies that platforms years In making. inthe one regard, timing the of the draft of virus’s the genome, built upon of decades research and and Infectious (NIAID) Disease just 6weeks after accessing a forvials clinical testing at USNational the Institute of Allergy extraordinary. RNA vaccine company Moderna was shipping The of pace development for vaccines against SARS-CoV-2 was Zipkin Mark their development. The COVID-19 pandemichasputnew vaccine technologies into thespotlightandaccelerated challenges but new possibilities, new New vaccine appro aches present c a | Recombinant protein vaccine plus adjuvant. mRNA-based vaccines Other factorsOther were important as well, Nabel says. For one, in The foundation for latest the wave of vaccine technologies spike protein into cells mRNA encoding theCOVID-19 transportLipid b Adenovirus-vector basedvaccines into cells encoding theCOVID-19 spike protein Adenovirus vectors carrytheDNA and Development Authority (BARDA), which handled vaccine of Health and Human Biomedical Services’ Advanced Research Emergency Use Authorizations (EUAs), and Department the (FDA), aclear regulatory path which carved for vaccines via Speed toSpeed push Moderna’s COVID-19 vaccine through phase 2 clinic.the Still, it took nearly $1billion from Operation Warp BioNTechstage while clinical trials, had 6cancer vaccines in of pandemic, the Moderna had 11vaccines or therapies inearly- IPO, the biggest ever for abiotechnology company. eve On the and endeavoring to live up to it. In 2018, it a $604million closed . a viral make antibodies, mimicking natural the immune response to to produce protein, the recognize it as aforeign antigen and invade human The cells. mRNA vaccines prompt human cells SARS-CoV-2 spike protein, to needs which bind virus the and aprotein—inencodes of case the COVID-19 vaccines it is the distribution of vaccines for COVID-19 inMarch 2020.mRNA clinical development, manufacturing, commercialization and notherapy company BioNTech, which partnered with for Pfizer mRNAthe platforms pioneered by Moderna and German immu- approveda fully vaccine USA(Fig. 1). inthe FDA are built on platforms haven’t that still new so they produced three COVID-19All vaccines that have issued EUAs been by the Pandemic proving ground procurement under Operation Warp Speed. Moderna spent years exciting investors with its mRNA platform The first two COVID-19 vaccines granted an EUA are on based | Nucleic acid vaccines. c Recombinant protein vaccines are administered withan adjuvant recombinant COVID-19 spike proteins coatedNanoparticles with b | Adenovirus-based vaccines. www.nature.com/biopharmdeal |June 2021 | FEATURE B3 Credit: KamilSD / Alamy Stock Photo FEATURE

and phase 3 clinical trials. Operation Warp Speed also signed a mRNA vaccines are delivered in lipid nanoparticles, meaning manufacturing agreement worth up to $1.525 billion in August they don’t trigger the same immune response over multiple doses. 2020. BioNTech and Pfizer signed a $2 billion manufacturing As additional, resistant viral SARS-CoV-2 strains have emerged, contract for their COVID-19 vaccine through Operation Warp mRNA companies have quickly developed boosters against the Speed in July 2020, but did not receive R&D funding. variants. But the lipids can still trigger some inflammation and The adenovirus platform at Johnson & Johnson’s Janssen unit immune response. “I suspect that’s at least part of the reason why that produced the third SARS-CoV-2 vaccine to receive an EUA, people get these side effects when they get an mRNA vaccine,” said JNJ-78436735, was slightly more mature, having scored its first Nabel, though he adds that can likely be improved in the future. European Commission approval last July with the vaccine Today most mRNA vaccines have stabilization issues that Zabdeno. Adenovirus vaccines have been tested in the clinic require ultracold storage throughout the supply chain. That for years, but had struggled to take hold until recently. In the requires sophisticated logistical solutions, said Philippe Denoel, 1990s, adenoviruses were explored as delivery vehicles for gene Head of External R&D for GlaxoSmithKline (GSK) vaccines. “We therapies in diseases such as cystic fibrosis, but their tendency have all seen in one year how important this technology platform to provoke an immune response was more desirable in a vac- is, it allows very fast development of vaccine candidates. But it’s cine. The vaccines are based on recombinant adenoviruses, not going to be the one and only solution for the future.” modified to block their ability to replicate or cause illness, that deliver genes for producing an antigen—again, in the case of The next wave JNJ-78436735 and others using viral vectors that have received All of the current platforms have their limitations, which has regulatory approval in countries outside the USA, that means kept academics and companies looking to improve on or build the SARS-CoV-2 spike protein. on existing technology. One area of broad possibility is adjuvants, One benefit to an adenovirus vector such as type 26 (Ad26) which only recently began to advance beyond traditional adju- used in J&J’s vaccine is that “it’s a relatively easy virus to work vants resembling those used in vaccines since the 1930s. Adjuvants with, to insert antigens in, and to make lots of vaccines with,” improve the potency of vaccines by boosting immune responses, said Jay Nelson, director of Oregon Health & Science University making them extremely important for vulnerable populations, (OHSU)’s Vaccine and Gene Therapy Institute. Another is that including the elderly, that have reduced immune function, said the body recognizes it as a pathogen and mounts an immune Nelson. At least one COVID-19 vaccine candidate nearing response. potential regulatory authorization, ’s NVX-CoV2373, combines a full-length SARS-CoV-2 spike protein in a recombi- Testing the limits nant with a saponin adjuvant, and it has been highly There is a flipside to the body’s pointed immune reaction to viral efficacious in phase 3 testing. vectors that could limit their effectiveness though. “When you Another example is Shingrix, a vaccine developed from GSK’s use a , you have to worry about two things: how preva- AS01 adjuvant platform and approved by the FDA in 2017 to pre- lent that virus is in population, and if you give repeat administra- vent shingles in adults aged 50 years and older. AS01 is a liposome- tion, whether that could give an adverse response,” said Nabel. based adjuvant with two immunostimulants that GSK has also According to Nabel, the immune system responds to both the used to develop a , Mosquirix, which is approved adenovirus and the inserted gene, meaning anyone previously in Europe. “We’ve seen with Shingrix that using an adjuvant has exposed to the natural variant of that adenovirus strain would made all the difference between having an OK vaccine versus one generate antibodies to the vaccine. This pre-existing immunity that’s really quite effective,” said Nabel. to the vector effectively reduces the dose, and Nabel thinks it’s Denoel says investments in the AS01 platform also led to the one reason why Janssen might have wanted JNJ-78436735 to be development of additional adjuvants such as AS03, which has a single dose: boosters may be less effective. “In many cases that been used to improve on GSK’s influenza and COVID-19 vaccine can be a limitation,” said Nabel, “because the immune system candidates. “The adjuvant platform has been a major investment seems to do better, in general, when it sees the same thing more for us in research and development over 25 years,” he added. than once. That’s how you generate memory responses.” Others are using the limitations of existing platforms to inspire For its part, Janssen—which has also tested Ad26 vaccines to new approaches. Nelson took cues from adenovirus research as prevent Zika, HIV, and respiratory syncytial virus (RSV)—has his team developed VIR-1111, an HIV vaccine delivered instead found no consistent pattern in clinical trials between base- by a replication-impaired, persisting cytomegalovirus. No adeno- line Ad26-neutralizing antibodies and immune response to virus-based vaccine for HIV has made it to phase 3 testing, and its vaccines. Nelson suggested that they are better suited for acute Other companies have attempted to lessen the issue by devel- like COVID-19. The cytomegalovirus approach “might be a way oping platforms based on adenoviruses that do not naturally to get around persistent infections, like simplex or other herpesvi- infect humans. AstraZeneca’s COVID-19 vaccine, Vaxzevria ruses.” Vir Biotechnology licensed the platform through a merger (AZD1222)—granted emergency authorization in the UK and with the OHSU spinout, TomegaVax and now has VIR-1111 in conditional approval in Europe earlier this year—was developed phase 1 trials. at the University of Oxford based on a chimpanzee adenovirus, Nabel also noted that nanoparticle technologies are promising ChAdOx1. “A lot of people in developing countries have already approaches. “In the lab, we can mount specific parts of virus to been infected with adenovirus, but they wouldn’t have been synthetic nanoparticles, which will spontaneously assemble and exposed to the chimpanzee one,” said Nelson. AstraZeneca has present them in an array to the immune system,” triggering a more not yet applied for an EUA in the USA. active immune response, he added. Other companies, including Still, said Nelson, exposure to the vector in one vaccine might Capricor Therapeutics and Codiak BioSciences, are developing prevent an effective immune response to any future vaccines made exosomes—naturally derived nanoparticles—as potential vaccine from that vector. delivery systems. And not all adenovirus vectors are the same. For example, GSK has several other vaccine technologies in development, says adenovirus type 5 (Ad5) has been utilized by China’s CanSinoBIO Denoel. One is through a partnership with LimmaTech Biologics, for its Convidecea vaccine, as well as in the booster following an to develop next-generation recombinant glycoconjugate vaccines. Ad26-based prime dose in Russia’s Sputnik V vaccine. But the The company is also tapping a structural biology platform, explor- approach has concerned some experts, including researchers who ing how vaccine antigens like the RSV prefusogenic fusion protein previously tested Ad5-based vaccines for HIV, who have linked structure and the coronavirus spike protein can inform future it to increases in HIV infection. vaccine development. / Anastasiia Zakhozhenko Credit: Vector Stock Alamy

B4 | June 2021 | www.nature.com/biopharmdeal FEATURE

Investing in the future because we knew that the NIH was going to be funding people Infectious disease research is a team sport, by any measure. “It’s in this direction. And that’s been quite successful.” The institute a different business model from other therapeutics,” said Nabel. has two contracts with NIH to develop new adjuvants—one of the The number of patients tends to vary, year on year, and vaccine institute’s priorities, he said—including one working with immu- trials require large sets of patients. notherapy company Inimmune. “The NIH has been extremely Funding for research and development is often bolstered by helpful in forming these types of partnerships, which I think are public bodies and public–private partnerships. Partnership is really necessary to get new vaccines out there,” he said. foundational to GSK’s approach, says Denoel, and support from Still, there are some things that can’t be done in an academic the Bill & Melinda Gates Foundation and other funders was lab. It was the Gates Foundation, working with OHSU on its HIV crucial for development of Mosquirix. He also noted that the vaccine, that pushed several OHSU researchers to co-found Vir, , and public funders like BARDA and the NIH said Nelson, which raised $143 million in an IPO in 2019 and now have been necessary for GSK’s work on Ebola, and the Innovative has a market cap of $6.3 billion. “We couldn’t take it any further, Medicines Initiative—a public–private partnership developed by we needed somebody that had expertise in vaccine manufacturing the European Commission—brings an important support to the and clinical trials,” Nelson added. development of new pertussis and RSV vaccines. Pre-pandemic, private investment had been more supportive of The European Commission is also launching its response to viral vaccine-adjacent companies, like BioNTech and Moderna, BARDA, the European Health Emergency Preparedness and which focused more in areas like immunotherapy. “I wish that it Response Authority (HERA), this year. Denoel called this a welcome could be the reverse, that thanks to investments in infectious dis- addition to the world of biopreparedness. ease, or biopreparedness vaccine technologies, this could instead Public funding in particular has been notable in the past year open up opportunities for the treatment of other important situ- as governments signed huge procurement deals that provided ations like oncology, antibiotic resistance or non-communicable the financial incentives to get COVID-19 vaccines across the fin- diseases” said Denoel. He remains optimistic, however. “I think ish line, such as the $456 million vaccine order signed in March the situation has somewhat changed, they realize that infectious 2020 by Johnson & Johnson—before its clinical trials had even disease offers not only opportunities to bring solutions to impor- begun—with BARDA. But Vered Caplan, CEO of personalized tant medical needs and , but also could translate into cell and gene therapy company Orgenesis, notes that many vac- some kind of financial returns for them.” cine technologies, including mRNA, might not exist without Viral vaccines remain risky business, though. “We’ve had a little basic research funding from NIH. “We should look at where bit of an infusion of talent and resources,” said Nabel. “I don’t these technologies are coming from,” she said. “This is taxpayer know how long that will last. The same thing happened with money being invested into academic institutes. This information Ebola—as soon as it was no longer a threat, everybody said, belongs to everyone, in a way we don’t always realize.” ‘Forget that, who wants to work on Ebola vaccines?” Only time NIH priorities guided the creation of Nelson’s institute two will tell whether COVID-19 has the same fate. decades ago, down to the interdisciplinary staff he recruited. “I hired in people that would have their own programs,” he said, Mark Zipkin is a freelance writer covering the pharmaceutical “but the idea was, we would all work together on programs, and biotech industries.

www.nature.com/biopharmdeal | June 2021 | B5