COVID-19 vaccines could soon be authorized, and optimism reigns, but putting a stop to the pandemic will be a long haul effort.Credit: Simon Kadula / Alamy Stock Photo

Just 200 days after beginning a clinical development program for their COVID-19 vaccine, Pfizer and BioNTech submitted a request to US drug regulators for an emergency approval.

The application to the US Food and Drug Administration (FDA) came on 20 November, soon after the companies found in a phase 3 study that their messenger RNA (mRNA) vaccine was 95% effective — including in the elderly, a population particularly vulnerable to SARS-CoV-2. The companies wrapped up their study of >43,000 people when the number of confirmed COVID-19 cases reached 170, with 162 of those occurring among people given placebo shots. If granted an Emergency Use Authorization, Pfizer and BioNTech say they will begin offering the BNT162b2 vaccine to healthcare workers and high-risk populations in the United States as soon as mid-December.

Moderna, the other leading developer of an mRNA-based COVID-19 vaccine, might not be far behind. On 30 November, the company filed its own application to FDA authorities on the basis of phase 3 trial data from 196 cases, 185 of which arose in the placebo group, yielding a point estimate of vaccine efficacy of 94%. The FDA's Vaccines and Related Biological Products Advisory Committee is expected to review the data packages for BNT162b2 and Moderna's mRNA-1273 on meetings scheduled one week apart in mid-December. No mRNA vaccines have ever reached this late stage of clinical development.

“All of these data show the promise and potential of messenger RNA vaccines as a new modality in the vaccine field,” says Mariola Fotin-Mleczek, chief technology officer of CureVac, another mRNA-focused company. CureVac is on track to initiate phase 3 testing of its COVID-19 vaccine by the end of the year.

Still, much about the vaccines’ efficacy and safety — biological details that could shape the course of the vaccines’ impact on containing the pandemic — remain unknown. “Personally, I’m waiting for further data concerning T-cell responses and duration of the antibodies,” says Stanley Plotkin, a pioneering vaccinologist and former pharmaceutical executive who now consults for vaccine manufacturers. And while acknowledging that the data reported to date are “very encouraging,” Plotkin is reserving judgment on the mRNA vaccines until more results become available from late-stage trials of the many other experimental vaccines now moving their way through clinical development.

Of the other vaccine types, two adenoviral vector–based candidates — AZD1222 from AstraZeneca and the University of Oxford, UK, and Sputnik V from the Gamaleya National Center of Epidemiology and Microbiology in Moscow and the Russian Direct Investment Fund — have already reported preliminary phase 3 data. More results are expected soon for vaccines built around recombinant proteins, inactivated versions of SARS-CoV-2 and other technologies as well. “By the end of next year,” Plotkin says, “we’re going to have really concrete comparative data.”

The two mRNA front-runners share many commonalities. Both take advantage of modified RNA chemistry to encode the SARS-CoV-2 spike protein with stabilizing mutations added to lock the shape-shifting surface protein into a form easily recognizable to the immune system. Both also use lipid nanoparticle (LNP) delivery systems. Efficacy results reported for each vaccine were based on similar analyses — the number of participants who developed symptoms of COVID-19 and then had laboratory confirmations of infection, either one week after receiving the second of two vaccine doses spaced three weeks apart, in the case of the Pfizer/BioNTech trial, or two weeks after a two-shot, 28-day regimen with the Moderna vaccine.

Despite the many molecular and clinical parallels, however, the two products have shown key distinguishing features as well.

On the safety side, while both BNT162b2 and mRNA-1273 were generally well tolerated by participants of phase 3 trials, with most side effects short-lived, the Moderna vaccine was linked to a greater incidence of severe adverse events such as a fatigue and muscle pain after the second shot. Experts speculate that the different dosages (30 micrograms for BNT162b2 versus 100 micrograms for mRNA-1273) could account for the different tolerability profiles.

The Pfizer/BioNtech vaccine might also have a slight edge when it comes to the immune response. In phase 1 trials, with both vaccines, humoral immunity was strong, with virus-neutralizing antibody titers generally surpassing those found in individuals who had recovered from natural infection. As for cellular immunity, both also induced CD4+ T-cell responses skewed toward T-helper type 1 cells. Yet, as reported, only the Pfizer/BioNTech vaccine seemed to bring about any sort of cytotoxic CD8+ T cell response. Direct comparisons are difficult, however, as the two vaccine developers used different assays for profiling immune cells.

Where Moderna could have the upper hand is in distribution and storage infrastructure. The company claims that its vaccine remains stable in a standard –20 °C freezer for up to six months, under refrigeration (2–8 °C) for up to 30 days and at room temperature for up to 12 hours. By comparison, Pfizer and BioNTech plan to keep their vaccines at the arctic temperature of –70 °C. To maintain that ultracold temperature in transit, they have created specially designed shipping containers that, if replenished with dry ice, can be used for up to 15 days; otherwise, specialized freezers costing upwards of $10,000 are needed. Once thawed, the companies say, the vaccines can last for up to five days in the fridge.

While it’s possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences, many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions. “I don’t think there’s any reason to assume that any of them will be different in terms of their stability,” says Tom Madden, president and CEO of Acuitas Therapeutics in Vancouver, British Columbia, the company behind the LNPs used in the COVID-19 vaccines from Pfizer/BioNTech and CureVac. Describing the –70 °C cold chain as “most conservative approach,” Madden notes that more long-term data, presented in full rather than in a press release, are needed to resolve the issue.

“Different companies have taken different approaches to how they’re going to roll out the vaccines, and we’re seeing that in the press releases,” Madden says. But, “as I like to say, you can’t run a two-year stability study in six months — and that’s the reality of the situation.”

Still, the initial cold-chain requirements for BNT162b2 could hamper the vaccine’s distribution or lead to spoilage, especially in parts of the world without reliable electricity infrastructure. According to Philip Dormitzer, head of viral vaccines research at Pfizer, the company has ongoing thermostability studies and is working on a lyophilized formulation as well. While research into that process continues, however, “we are focused very much on distributing with what we know we can do,” Dormitzer says. “That’s the lowest risk approach.”

Both leading mRNA vaccines could also face supply chain challenges. In addition to securing the requisite number of glass vials, syringes and other consumables involved in the fill–finish part of the vaccine manufacturing process — plus the dry ice and cold packs needed for distribution — the products will demand unprecedented quantities of more exotic ingredients, such as the capping enzyme needed to stabilize the mRNA after transcription from its DNA template. Jake Becraft also worries about having sufficient raw materials for the multicomponent LNP systems. “There’s not going to be enough cholesterol for the lipid nanoparticles,” says Becraft, cofounder and CEO of Strand Therapeutics, a synthetic biology company developing mRNA-based medicines, including a COVID-19 vaccine candidate being tested in Asia.

Several biological uncertainties linger as well (Nat. Biotechnol. 38, 1132–1145; 2020). Both BNT162b2 and mRNA-1273 seem to prevent disease within a week of two of immunization. “The question is: What’s the durability going to be like?” says Philip Santangelo, a bioengineer who studies mRNA delivery at the Georgia Institute of Technology in Atlanta. In phase 1 studies of Moderna’s other mRNA vaccine products, researchers observed signs of lasting antibody persistence against some pathogens, such as cytomegalovirus, but waning immunity against others, including influenza. But, as Santangelo points out, immune persistence tends to be “very antigen specific, unfortunately” — which makes extrapolating to COVID-19 vaccines difficult. “It’s not predictable,” he says.

Dormitzer, for his part, takes comfort in the finding that the second dose of the prime–boost approach seems to trigger massive upticks in antibody levels, a sign that some type of immune memory has formed. So, he says, “at least we’ve got boostability if the durability isn’t as good as we hoped for.”

In principle, AstraZeneca’s adenovirus-based vaccine could have an advantage over mRNA-based products as it has good tolerability and could offer longer-lasting protection against SARS-CoV-2 infection. The company’s AZD1222 uses a non-replicating chimpanzee adenovirus to express the wild-type version of the spike protein, and other vaccine candidates built around the same vector platform and prime–boost strategy have led to immune responses persisting for a year or longer.

On 23 November, AstraZeneca and its partners reported interim data showing that their vaccine candidate was 70% effective overall, with that number rising to 90% among study participants given one particular dosing regimen. In their phase 3 trial, conducted in the United Kingdom and Brazil, 131 COVID-19 cases were recorded a fortnight or more after trial participants received the immunization and booster.

Earlier in the month, the team behind Sputnik V similarly announced, on the basis of 39 COVID-19 cases identified in an ongoing phase 3 trial, that its product looked to be 91% effective. That vaccine — which already received emergency approval from Russia’s Health Ministry — involves a prime–boost regimen of two recombinant adenovirus vectors, a type 26 followed by a type 5 three weeks later, each encoding the wild-type spike protein. According to a Russian Direct Investment Fund spokesperson, trial results will be submitted for publication in a peer-reviewed journal in the coming weeks.

Whichever vaccine platform’s immunity proves more durable could ultimately have an outsized impact on the future trajectory of the coronavirus pandemic, says Caroline Wagner, a computational biologist at McGill University in Montreal, Quebec, who has modeled disease dynamics under various immunological scenarios. Whether the vaccines curb virus spread or simply keep people from becoming as sick upon infection will also be important, she notes — yet the effects on transmission remain unknown since the phase 3 trials were designed primarily to consider symptomatic disease.

If the vaccines don’t elicit transmission-blocking immunity, then initial public health campaigns focused on inoculating high-risk populations and the elderly — although they should help save lives — may not do much to bring the pandemic under control, according to vaccine allocation models developed by mathematical biologists Daniel Larremore and Kate Bubar at the University of Colorado Boulder. And even once the general population starts getting the vaccines, it may not fully obviate the need for social distancing and other mitigation strategies any time soon, especially if many people opt not to roll up their sleeves for the shots.

As Bruce Y. Lee, a health systems modeler at the City University of New York School of Public Health, points out: “You still have to get a high enough vaccination coverage for that to actually be able to halt the spread of the COVID-19 coronavirus.” According to Lee’s models, at least 70% of the population will need to be vaccinated or have been infected with SARS-CoV-2 to fully extinguish the pandemic. “That’s not an insignificant bar to try to reach,” Lee says.

Add in all the supply chain issues, vaccine skepticism and logistics of a two-dose regimen and it’s anybody’s guess which COVID-19 vaccine will ultimately deliver the biggest public health benefit. “The things that really start distinguish one thing from another are not the early promise — it’s how they do over the long run,” says Naor Bar-Zeev, a vaccine epidemiologist at the Johns Hopkins Bloomberg School of Public Health.

The contest to bring a COVID-19 vaccine to market often gets framed as a race, but “it’s not a sprint,” Bar-Zeev says. “It’s a long haul.”