The entire scientific community is cheering on Pfizer and BioNTech’s early COVID-19 vaccine data. Beyond the obvious boon for fighting the pandemic, the 90% efficacy result showed mRNA shots really can work.
For an entirely new technology that hasn’t seen a single approved product, that's a big deal; the coronavirus showing proved it can be quickly pivoted for a pandemic pathogen. But its usefulness in other diseases? That could be a different story, two industry watchers figure.
The early success of a COVID vaccine is going to “open the floodgates” of mRNA application especially in infectious disease, SVB Leerink analyst Daina Graybosch, who covers BioNTech, said in an interview.
Before the efficacy readout, the industry already knew the shot, dubbed BNT162b2, could elicit strong neutralizing antibody, binding antibody, CD4 and CD8 T cell responses. Although we still don’t really know which of those—or even an immune component the scientists didn’t measure—are driving the shot's efficacy, at least we know the vaccine very likely works for this infection, Graybosch said.
A flexible infectious disease platform, yes
That unknown has Graybosch balking at concluding other mRNA candidates, such as Moderna’s mRNA-1273, also work. The Pfizer/BioNTech data definitely shed a positive light on Moderna’s program, but the two platforms do have their differences.
For example, the Moderna shot didn't do as good a job as Pfizer's at boosting CD8 T cell responses, Graybosch noted. That might be because of the different assays researchers used to measure CD8—or there may be true platform differences causing the gap.
“BioNTech CEO Uğur Şahin has suggested that their platform has been optimized to getting more antigen expression directly in antigen-presenting cells in the spleen, and that is giving you a really strong CD8 T cell response,” Graybosch said.
Wolfe Research analyst Akash Tewari also resists the idea of lumping all mRNA technologies into a single "platform" basket.
“One of the things that stood out to me is how different the three mRNA approaches have been between Pfizer/BioNTech, CureVac and Moderna,” Tewari said. He pointed to the vaccines’ different “therapeutic windows”—meaning the optimal dosing—as well as BNT162b2’s CD8 T cell response.
For an mRNA vaccine, the genetic message encoding for the protein antigen needs to be effectively delivered into the cells. “That in and of itself is not easy to do, and that’s not necessarily a platform-type deal,” Tewari said.
The one thing the three do have in common is that “mRNA seems to be a really flexible platform in the context of COVID,” Tewari added. During early research work, BioNTech had about 20 candidates, which they narrowed down to four before choosing BNT162b2. “That level of preclinical tweaks is not something you can do with other technologies,” he said.
In an infectious disease, we know now that mRNA can be quickly pivoted to make really complex antigens. “What mRNA proved here was the ability to get products quickly into the clinic and then also to experiment with different preclinical versions over a relatively short period of time to figure out what type of immune signature you want to take forward,” Tewari said. “And also it shows that mRNA can induce a lot of different immune signatures as well.”
Graybosch brought up GlaxoSmithKline’s shingles vaccine Shingrix, which needs an adjuvant to provide a good balance of T cell and antibody responses. “And now we have a second platform that looks like it can give you that,” she said. “So I think that we’re going to see just a ton of more effort here and it’s going to accelerate.”
Other diseases? Too early to tell
But even in infectious disease, Tewari cautioned that mRNA vaccines' power could be specific to antigens. The majority of COVID-19 vaccine candidates are focused on the novel coronavirus’ spike protein, which plays a key role in infecting human cells. It just so happens to be an immunodominant antigen, which means it can attract the immune system to launch an attack and is therefore an ideal target for a vaccine.
But there are other pathogens whose harmful regions are hidden, while the less critical components divert the immune system. That could present difficulties for mRNA, as well as other, more traditional vaccine technologies.
Graybosch also argued that the extent of positive read-through from the Pfizer/BioNTech data to future mRNA vaccines depends on individual vaccine targets. It's most promising “for settings that require very fast turnaround for novel antigen,” such as a pandemic or even a flu season dominated by an unexpected viral strain.
Therapeutic areas outside of infectious disease could be even more difficult to predict. Cancer is a major focus for BioNTech and Moderna, but picking the right tumor-specific neoantigen has been a challenge for all cancer vaccines, Graybosch noted. And there are tumors that cancer vaccines, due to the limitation of the immune response they can induce, cannot tackle, Tewari noted.
Indeed, mRNA’s flexibility, and its ability to induce multiple types of immune response, are impressive, “but it would be scientifically irresponsible to say COVID data means that the cancer vaccines are going to definitely work,” Tewari said.
A rare opportunity for acceleration
The heavy government investment into mRNA-based COVID programs significantly accelerated the companies’ R&D process—and they helped cover costly manufacturing scale-ups. “I think the biggest thing this does is it gives them cash to do the experiments they want to do,” Graybosch said.
Unlike infectious disease, immuno-oncology takes a long time to deliver a signal, and investors don’t necessarily buy-in. Before COVID, BioNTech was focused on cancer; now, Graybosch figures the company will have more infectious disease programs to provide “a continual inflow of cash to support the longer-term, more challenging, more risky efforts in immuno-oncology,” she said.
What’s more, the rise of mRNA as a new, validated vaccine platform could shake up the traditional positioning of the “Big Four” vaccine moguls, namely Sanofi, GSK, Merck and Pfizer, Graybosch argued. “There are some new players emerging here” that, because of their COVID work, “are going to have manufacturing and a lot of scale and experience,” she said.
For now, the four giants have all partnered up on mRNA. Pfizer has its BioNTech partnership. GSK picked CureVac to work on up to five mRNA-based vaccines and monoclonal antibodies. Merck has an ongoing oncology collaboration with Moderna, though the New Jersey pharma recently returned an RSV candidate. And Sanofi recently doubled down on its investment in Translate Bio.