COVID-19 and Mrna Vaccines—First Large Test for a New Approach

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Medical News & Perspectives COVID-19 and mRNA Vaccines—First Large Test for a New Approach

Jennifer Abbasi

n January 10, Chinese researchers posted the novel coronavirus’ RNA O sequence on a preprint server. Im- mediately,scientists who study genetic vaccines turned their efforts to the emerging pathogen that causes coronavirus disease 2019 (COVID-19). They knew that rapid response genetic platforms could shave pre- cious weeks to months off development, crucial during a pandemic. They were right. When the first US clinical trial for a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) began just 66 days later, volunteers received mRNA-1273, a messenger RNA (mRNA) candidate codeveloped by bio- technology company Moderna, Inc and the National Institute of Allergy and Infectious Diseases (NIAID). On July 27, based on encouraging early results, mRNA-1273 and another mRNA vaccine candidate, BNT162b2 from BioNTech and Pfizer, both entered phase subunit vaccines and virus-like particles, The viral vector technique transports 3 trials, which to- like in the hepatitis B and human papillo- genetic information in a less harmful virus— getherwillenrollan mavirus vaccines. often a common cold–causing adenovirus— Audio and Video estimated 60 000 Gene-based vaccines take a different that’s sometimes engineered so it can’t rep- volunteers. The milestone came “at a tack. They carry the genetic instructions for licate in the host. DNA and mRNA vaccine remarkably rapid pace compared to the the host’s cells to make the antigen, which designs deliver naked nucleic acids or, more usual pace for vaccine preparation,” more closely mimics a natural infection. recently, encapsulate them in a carrier National Institutes of Health (NIH) Direc- In the case of coronaviruses, the antigen of nanoparticle. Within each of these versatile tor Francis Collins, MD, PhD, said at a press interest is the surface spike protein the platforms, the same production and purifi- briefing that day. Results could be avail- virus uses to bind and fuse with human cation methods and manufacturing facili- able as early as this fall, NIH officials said. cells. “You’re not giving them the protein— ties can be used to make vaccines for differ- Despite the unprecedented speed, you’re giving them the genetic material that ent diseases. mRNA vaccines are clinically unproven. No then instructs them how to make that spike Thesehighlyadaptabletechniqueswere commercially available vaccines use the plat- protein, to which they make an antibody waitinginthewingswhenCOVID-19hit.“The form and, until now, it hasn’t been tested in response that hopefully is protective,” people who jumped on this right away are large-scale human trials. With COVID-19, University of Pennsylvania vaccinology pro- the people who had vaccine platforms that that’s all set to change. Experts said in inter- fessor Paul Offit, MD, explained in a JAMA were conducive for this that were simply sit- views that if the technology pans out, the livestream in June. ting there,” said Louis Picker, MD, associate pandemic could help to usher in a new plug- The approach isn’t entirely unfamiliar. In director of the Oregon Health & Science Uni- and-play approach to vaccinology. live-attenuated vaccines, like the measles, versity’s Vaccine and Gene Therapy Insti- mumps, and rubella shot, weakened vi- tute. “Allthey had to do is basically figure out The Genetic Advantage ruses incorporate their genetic instructions what part of [the virus] they were going to Current antiviral vaccine designs can into host cells, causing the body to churn out put in the vaccine and then run with it.” be described as falling into 2 camps: pro- viral copies that elicit antibody and T-cellre- Thanks to research beginning in 2002 tein based or gene based. Protein-based sponses. In newer gene-based designs— on the severe acute respiratory syndrome vaccines deliver the immune system– viral vector, DNA, and mRNA vaccines— coronavirus and then the Middle East respi- stimulating antigen to the body. This cat- scientists synthesize and insert genetic ratory syndrome coronavirus, which egory includes whole-inactivated (killed) instructions from the pathogen of interest to emerged a decade later, scientists knew to

Paul Hennessy/AP Images vaccines, as in the polio and flu shots, and induce immune responses. focus their initial attention on the novel

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coronavirus’ spike protein. They also al- University of California, Los Angeles, David passes that step. “Ninety-five percent of cells ready knew which genetic modifications Geffen School of Medicine, the body’s cells that meet the RNA take it up and make pro- would stabilize the spike in its “prefusion” only display viral proteins on their surface tein, so it’s an incredibly efficient process,” configuration—important for a robust and through this pathway if those cells them- Weissman said. safe antibody response—and those that selves have produced the proteins. “If you would make the mRNA less inflammatory just inject a protein or inject a dead virus, it Proof Is in the Pudding and therefore safer. They had also learned doesn’t get into that pathway and doesn't The first 4 COVID-19 vaccine developers how to purify mRNA to rid it of contami- get displayed that way, and so the T cells with published clinical trial data all used nants and how to protect it from degrading don’t get stimulated,” he said. either a non–replicating adenovirus or too quickly in the body by encasing it in lipid Even among the gene-based plat- mRNA platform. The US government is bet- carriermolecules.Thesedeliveryvehicles,al- forms, distinct advantages exist. In cutting ting on some of these new technologies. ready in use with therapeutic small interfer- out the viral vector, both DNA and mRNA Under the auspices of its Operation Warp ing RNAs, also help mRNA cross the cell vaccines eliminate the risk of preexisting im- Speed vaccine development initiative, it membrane and may even have an immune- munity against it, which can limit effective- has already purchased hundreds of millions stimulating adjuvant effect. ness. “If your immune system clears a vec- of doses of ChAdOx1 nCoV-19, mRNA-1273, Many of these innovations weren’t tor before it will actually get into the cells, BNT162b2, and an investigational non– possible until recently, according to Barney that’s a big problem,”Yang said. Such immu- replicating viral vector vaccine in early trials Graham, MD, PhD, deputy director of the nity could also be more common in some from Johnson & Johnson–owned Janssen NIAID Vaccine Research Center. “Over the geographic areas than others, rendering a Pharmaceutical Companies, as well as other last 10 years, vaccinology has just changed vectored vaccine more or less effective de- candidates. Doses should be standing by if radically,” he said. “I’ve been doing this kind pending on the region. or when any of these are approved. of work for a long time and the kinds of Preexisting immunity could explain All eyes are now on safety and effective- things that can be done now, the technolo- why a non–replicating viral vector COVID-19 ness. Non–replicating viral vector vaccines, gies available, the way we can understand candidate from CanSino Biologics Inc and whilearelativelyrecentapproach,havebeen things in a very detailed level is really stun- several Chinese institutions elicited less- studied extensively in HIV and other dis- ningtome.” than-impressive neutralizing antibody lev- ease trials. Janssen’s new Ebola vaccine regi- Unlike conventional vaccines, mRNA els in a phase 1 trial. Preexisting neutralizing men, which uses 2 different non–replicat- vaccines aren’t grown in eggs or cells, a time- antibodies to the vector, the human adeno- ing viral vectors, received European consuming and costly process. At their es- virus 5, known as Ad5, ranges from up to authorization in July. sence, these vaccines are simply chemicals 69% in the US to 80% in Africa. Of addi- mRNA vaccines haven’t been clinically catalyzed in test tube or a tank. This makes tional concern, Offit said in an August testedtothesameextent,though.Research- them easier to develop quickly and—at least livestream, more than a decade ago, men ers have studied investigational mRNA- theoretically—at scale, although they’ve with preexisting Ad5 immunity had an based therapeutic antibodies and therapeu- never been mass-produced before. increased risk of acquiring HIV infection ticcancervaccines.ButGermanfirmCureVac “We were making RNA within a week or after receiving an experimental Ad5- and academic collaborators published phase so” of the SARS-CoV-2 sequence being pub- vectored HIV vaccine. 1 results from the first prophylactic mRNA lished, said Drew Weissman, MD, PhD, who To get around these issues, ChAdOx1 vaccineclinicaltrial,foracandidateagainstra- researches mRNA vaccines at the Univer- nCoV-19, a non–replicating viral vector can- bies, less than 3 years ago. sity of Pennsylvania Perelman School of didate in phase 3 trials from AstraZeneca and Since then, potential mRNA vaccines Medicine. That speed propelled develop- the University of Oxford, uses an adenovi- against rabies, influenza, Zika,andafew ment: according to Weissman, both groups rus that infects chimpanzees instead of hu- other viruses have been studied in small, currently testing nucleic acid-based vac- mans. But, it’s possible that cross-reacting early-phase trials, many of which are still un- cines in phase 3 trials licensed his team’s preexisting immunity to human adenovi- derway. In both rabies and influenza trials, mRNA formulation from the university. ruses could still diminish the response. the candidates stimulated promising but According to Weissman, mRNA vac- lower-than-expected neutralizing antibod- Why mRNA? cines also have a leg up on DNA vaccines. In ies. Some moderate and severe injection site As of August 20, thirty potential vaccines a DNA vaccine, the genetic material must or systemic reactions were reported, al- against COVID-19 were in clinical trials, with first enter the host cell’s nucleus. From though severe events were rare. another 139 in preclinical development, in- there, messenger RNA is created, which So far, in early COVID-19 trials, mRNA cluding both gene- and protein-based can- travels out of the nucleus into the cyto- platforms have turned up encouraging didates. But genetic approaches have a po- plasm, where protein is formed from it. results. “Certainly, these vaccines look like tential immunological advantage. In addition However, genetic information can only they’re generating the immune response to eliciting antibodies and CD4+ helper enter the nucleus when the cell is dividing, that we need, and the reaction profiles T cells, they recruit CD8+ cytotoxic T cells, making the process inefficient. have not been associated with severe reac- also known as killer T cells, through the ma- Researchers are trying to solve this tions,” said Kathryn Edwards, MD, scientific jor histocompatibility class I pathway. problem using electric pulses to increase director of the Vanderbilt Vaccine Research According to Otto Yang, MD, an infec- DNA uptake into cells at the time of vacci- Program. But, she continued, “the real tious disease researcher and clinician at the nation. But the mRNA platform simply by- proof of the pudding will be the phase 3

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trials where we see if the vaccine actually couldhelptoovercomethis,Yangnoted,and pens, we’ll have a vaccine already made, prevents disease.” The US Food and Drug their cell-mediated immunity should pro- ready to be shipped out and used very Administration has said that a COVID-19 vide additional oomph. quickly to prevent the pandemic from tak- vaccine will need at least 50% efficacy to Offit, who is a member of an NIH Accel- ing over.” be approved. erating COVID-19 Therapeutic Interventions Before COVID-19, his team was work- Tolerability could be another issue. and Vaccines working group, said that how ing on mRNA flu vaccines, as well as candi- “People will have to know that they may long protection from any COVID-19 vaccine dates for genital herpes and HIV. Influenza have some local reactions or feel like lasts likely won’t be known until after a prod- viruses acquire variations from season to they’re a little under the weather for a day uctisapprovedandputintouse.But,asPicker season, making them excellent candidates or so after the vaccine,” said Edwards, who put it, a vaccine that’s safe and effective for for a rapid “vaccine on demand” platform. is among the independent experts monitor- evenafiniteamountoftimecouldbeenough In Weissman’s view, mRNA has the ing investigational COVID-19 vaccine safety. to “break the back of the pandemic.” potential to be truly transformative. In a She and others said that, as with any new soon-to-be-published study, he said he pharmaceutical product, phase 3 studies Beyond COVID-19 combined mRNA for 20 antigens for differ- could also reveal more serious safety con- If an mRNA vaccine works, the implications ent diseases in the same vaccine. All 20 cerns and unexpected adverse effects could stretch far beyond COVID-19. Suc- elicited good responses in mice. In theory, could emerge later. cess could pave the way for the platform’s he said, it might one day be possible for Speaking at the July 27 media briefing, widespread use for both emerging and es- children to get 2 shots that cover their Collins addressed concerns: “Yes, we’re tablished pathogens. more than 50 vaccinations. going fast. But, no, we are not going to “We are really making great strides in He’s not alone in that belief. The compromise safety or efficacy.” Experts say vaccine development, which will hopefully authors of a recent review article wrote several factors argue for mRNA vaccines’ change the way vaccines are approached in that mRNA vaccines that “can simultane- safety. For one, mRNA can’t cause an infec- the future,”said Amesh Adalja, MD, a senior ously target multiple antigens, and patho- tion. It also doesn’t enter the cell’s nucleus, scholar at the Johns Hopkins University Cen- gens will have broad utility for a range of so the chance of its integration into human ter for Health Security. diseases, reduce the number and fre- DNA is believed to be very low. In addition, One such advance might be thermo- quency of vaccinations, and alleviate the body breaks down mRNA and its lipid stable vaccines that don’t have to be frozen healthcare worker burden.” carrier within a matter of hours, assuaging or refrigerated, something scientists say Much of this could rest on the success some concerns about long-term risks. mRNA might enable. Chinese researchers or failure of an mRNA COVID-19 vaccine— However, this rapid degradation raises recently showed that a potential mRNA- and hopes are high. “I think this is an op- questions about mRNA vaccines’ protec- based SARS-CoV-2 vaccine could be stored portunity for that technology to shine,” tive duration. Of added concern for vaccine at room temperature for at least a week. Yang said. durability, researchers in Hong Kong re- Weissman is trying to develop a more Additional Reporting: Elena Guobyte. cently confirmed that a man with SARS- potent second-generation mRNA vaccine Note: Source references are available through CoV-2 was later reinfected, although his sec- that protects with a single shot. He’s also set embedded hyperlinks in the article text online. ond case was asymptomatic. Yang and his sights on a universal coronavirus vac- Accompanying this article is the JAMA Medical colleagues found that antibodies rapidly cine using the genetic platform. “We’ve had News Summary, an audio review of news content appearing in this month’s issues of JAMA. To listen wane among patients with mild COVID-19. 3 coronavirus epidemics in the past 20 to this episode and more, visit the JAMA Medical The current candidates’ 2-dose regimens years,” he said. “The next time this hap- News Podcast.

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