By Alejandra Manjarrez
Both of the mRNA vaccines available in the US are highly effective against severe COVID-19, but recent studies suggest that Moderna’s elicits a stronger immune response and might be better at preventing breakthrough infections. The two mRNA vaccines available in the US have proved to be highly effective against severe COVID-19.
Research published in recent weeks, however, suggests the Moderna vaccine’s advantage in terms of long-term protection. In multiple independent studies, significantly lower antibody levels and more vaccine breakthrough infections have been detected in the Pfizer/BioNTech-vaccinated population. These could be explained by a myriad of slight differences between the vaccines themselves: their distinct dosages, the intervals between the two doses, or the composition of the lipid nanoparticles used in each one. For now, all possibilities remain open.
By comparing vaccines and exploring the basis of their differences, “we are going to learn a lot in terms of what are the optimal strategies for vaccination,” says immunologist Alessandro Sette of the La Jolla Institute for Immunology in California, adding that there may not be one clear winner. “Some platforms may have some advantage[s] in terms of how fast the response develops, other[s] may have advantage[s] in how durable or how strong the response is,” he says.
Breakthrough infections: advantage Moderna
On the surface, the vaccines are very similar. Both are composed of lipid nanoparticles filled with mRNA. When these mRNAs get into cells, the cells begin to produce the non-infectious viral spike proteins they code for, which then trigger an immune response that trains the immune system to recognize the virus’s spiky exterior, so that it can launch a swift defense against the real virus.
And at first, these similarities seemed to extend to how well each vaccines worked. Early results found that both Pfizer/BioNTech’s and Moderna’s mRNA-based vaccines were outstanding at preventing COVID-19—results from Phase 3 clinical trials, which followed up participants for two months after they received their second shot, demonstrated an efficacy of 95 percent for Pfizer/BioNTech and 94.5 percent for Moderna. In the US, near 100 million people have been fully vaccinated with Pfizer/BioNTech and near 68 million with Moderna.
But more recent data have started to suggest a divergence in performance. For instance, a medRxiv preprint first published August 8 reports significantly fewer breakthrough infections among Moderna vaccine recipients than a similar cohort of participants that received Pfizer/BioNTech’s.
The study analyzed data from people who underwent SARS-CoV-2 PCR testing at the Mayo Clinic Health System in Minnesota from January to July 2021. Within the population available, they matched patients of similar age, same sex, race, ethnicity, SARS-CoV-2 testing history, and date of vaccination (if applicable) from three different groups: those vaccinated with Moderna, those with Pfizer/BioNTech, and those unvaccinated. This matching exercise resulted in groups of between 21,000 and 25,000 individuals for each of the three vaccination categories.
The team then assessed how the mRNA vaccines protected individuals from COVID-19 and found that, while SARS-CoV-2 positive test results were rare among those vaccinated compared to the unvaccinated group (38 infections in those who received Moderna’s, 72 for Pfizer/BioNTech’s, and 321 among the unvaccinated), the Moderna cohort had significantly fewer of them. The estimated effectiveness of Moderna at preventing infections was 86 percent versus 76 percent in Pfizer/BioNTech, and when they expanded the data to four other US states, they saw a similar trend: the numbers altogether showed a two-fold risk reduction of breakthrough infections conferred by Moderna’s vaccine when compared to Pfizer/BioNTech’s.
While differences in breakthrough infections—based on SARS-CoV-2 tests—were evident in their results, Venkatakrishnan and colleagues did not observe any significant differences in disease severity (based on variables such as hospitalization and death) between patients vaccinated with either mRNA vaccine. A study of 324,033 cases of SARS-CoV-2 infections in a community in Ontario, Canada, also failed to find significant differences in severe disease outcomes between groups fully vaccinated with either vaccine—though full vaccination, regardless of the brand, showed effectiveness of 98 percent against hospital admission or death. Recent reports from the Centers for Disease Control and Prevention (CDC), however, suggest Moderna’s vaccine could be also more effective at preventing hospitalization.
Estimated vaccine effectiveness in a CDC study of nearly 33,000 medical encounters between June and August 2021
Preventing ER/urgent care
MMWR Morb Mortal Wkly Rep 70:1291–1293, 2021
One of the CDC reports looked at 32,867 medical encounters from hospitals, emergency departments, and urgent care clinics across nine US states from June to August 2021. Based on these data, the authors estimated a higher vaccine effectiveness for Moderna (95 percent) compared to Pfizer/BioNTech (80 percent) for preventing hospitalization and, similarly, for preventing encounters at emergency departments and urgent care clinics (92 percent for Moderna and 77 percent for Pfizer/BioNTech). Another report by the CDC analyzed 3,689 cases of COVID-19 hospitalization across 18 states from March to August 2021 and estimated a higher vaccine effectiveness of Moderna (93 percent) versus Pfizer/BioNTech (88 percent).
Yet another study analyzed SARS-CoV-2 tests of patients admitted to a Yale New Haven Health System hospital from March 23 to July 1, 2021. A total of 969 patients tested positive, regardless of reason for admission, and of those, 14 were fully-vaccinated patients that developed severe or critical disease—13 between 71 and 95 years old who had received a Pfizer/BioNTech vaccine, and one 65-year-old female that had been vaccinated with the Moderna shots.
The research team did not do any statistics comparing those numbers, as they did not have the accurate knowledge of how these vaccines were distributed within the population attending the hospital, explains Hyung Chun, a medical doctor at the Yale School of Medicine and coauthor of the paper. He also expressed skepticism that the numbers stem from a real efficacy difference between the vaccines, noting that many factors could account for the 13-to-1 severe case number, including the fact that the Pfizer/BioNTech vaccine received approval for emergency use earlier than the Moderna vaccine.
“Both of these vaccines are highly effective, this happens to be our finding,” he says.
Epidemiologist and infectious diseases physician Imad Tleyjeh of King Fahd Medical City in Riyadh, Saudi Arabia, writes in an email to The Scientist that he does not think these clinical studies “provide strong evidence” of Moderna having higher effectiveness. Similar to Chun, he says that confounding factors could be driving the differences observed, for instance, “patients’ characteristics, mitigation strategies, circulating variants, time since vaccine intake and so on.” If these studies are replicated in different settings with similar findings, he adds, “then more likely this is a true observation.”
Immune activation: advantage Moderna
The slight differences between the vaccines’ behavior in the inoculated could suggest a more robust immune response to Moderna’s vaccine. Indeed, an increasing number of studies are comparing the vaccines by measuring recipients’ levels of antibodies that bind to the virus’s spike protein, a measure which correlates with levels of neutralizing antibodies and protection against a SARS-CoV-2 infection.
For instance, in the spring of 2021, a research team in a clinic in northeast Belgium decided to measure the antibody levels of the clinic’s health care workers following vaccination. Line Heylen, medical doctor at the Ziekenhuis Oost-Limburg who was involved in this study, says that the main motivation was to look at whether there were any individuals not developing immunity, to maybe consider a booster for them. Initially, comparing the two vaccines received by the 1,647 participants wasn’t the goal. But their analysis, published August 30, did find differences in performance between Moderna and Pfizer/BioNTech. Six to ten weeks after the second dose, patients who received Moderna’s vaccine had significantly higher concentrations of anti-spike antibodies.
The significant difference remained when they compared either only uninfected or previously infected patients, and also across different age groups. The previously infected is an interesting cohort, says Heylen, because they have such high antibody levels that the difference between the vaccines doesn’t really matter. Yet it was astonishing to see that the P value was significant. “I didn’t expect it,” she says.
The strongest difference in performance was among the clinic health care workers above 55 years old, previously infected or not. Those who received Moderna had 3.56 times more antibodies than those receiving Pfizer/BioNTech, according to Heylen. She is cautious to draw any conclusions, but based on these findings, she says that further research into whether any differences in performance are clinically relevant would be “very interesting.”
Another recently published analysis of a smaller cohort—167 adults affiliated with the University of Virginia—similarly found that differences in antibody production were most pronounced in older people, with Moderna eliciting a significantly higher immune response, especially in people over the age of 50.
Other small studies have also observed significantly higher antibody levels following Moderna vaccination, compared to Pfizer/BioNTech, in individuals with higher risk of severe COVID-19, such as patients on hemodialysis and liver transplant recipients. A study on cancer patients, in addition to finding lower antibody levels, detected fewer CD4+ T cells—immune cells that orchestrate the antibody response to infection—among the Pfizer/BioNTech-vaccinated cohort. They did not find, though, any significant differences between the Pfizer and Moderna shots in terms of the CD8+ T cells response—those that kill the infected cells.
Six to ten weeks after the second dose, patients who received Moderna’s vaccine had significantly higher concentrations of anti-spike antibodies.
While antibodies neutralize the virus and prevent infection, explains Sette, they cannot access the virus once it is inside cells. That’s where the CD4+ and CD8+ T cells come into play. They recognize infected cells, which may not be as important for preventing infections as for modulating and terminating them. These T cells likely have “a key role in avoiding severe disease and hospitalization,” says Sette. Thus, antibodies are not the whole story about immune activation, and more research will be need on other aspects of the response to these vaccines.
The big question: Why?
If further studies confirm the differences in antibody response and protection between both mRNA vaccines, an obvious question is: what could be driving them?
Xuhua Xia, a computational molecular biologist at the University of Ottawa who has previously analyzed the design of both vaccines, says that the slight differences in the mRNA sequences are not likely accounting for these potential differences in performance, as when translated, “they produce exactly the same protein.”
“Certainly the most striking difference is the [dosage],” says Sette. Each dose of the Pfizer/BioNTech vaccine delivers 30 µg of mRNA, while each of Moderna’s contains 100 µg.
It’s possible a higher dosage clinically translates into a more robust immune response and subsequent protection, a hypothesis Sette says “makes a lot of sense,” especially in light of what he and his colleagues found when they compared the immune response to two different mRNA doses of Moderna’s vaccine (25µg versus a 100µg). While the lower dose induced a good response in people—similar to that triggered by an actual SARS-CoV-2 infection—those who received it had significantly lower antibody levels and fewer CD4+ T cells two weeks after the second shot.
The interval between the first and the second dose is another variable that differs between the two vaccines: shots are spaced 21 days apart for Pfizer/BioNTech and 28 days apart for Moderna. “Multiple observational studies have shown that longer time intervals between priming and booster doses are associated with higher effectiveness,” writes Tleyjeh.
Both vaccines further differ in the fatty bubbles that carry the mRNA inside the body. In the lipid nanoparticles, “there may be some compositional differences that could perhaps contribute to it,” says Venkatakrishnan. Indeed, how the mRNA ends up distributed inside the body deserves further attention, says Xia, but as of yet, there’s no real data from human experiments to go off of.
There are also confounding factors stemming from the way the vaccines were rolled out. For example, as Chun noted for his team’s clinical data, the fact that Pfizer/BioNTech’s vaccine came out first could be a factor in retrospective studies, because it could mean timing or demographic differences between recipients.
Tleyjeh writes that in order to have a valuable comparison of both vaccines, “the gold standard study design . . . is a head to head comparative randomized trial. This design will avoid different types of biases and confounding.”
It’s unclear whether such a trial is warranted at this point, though, as both vaccines have already far exceeded initial expectations. After all, the initial cutoff for emergency use authorization from the FDA was 50 percent efficacy. Knowing which is slightly
better could be helpful “if we have equitable vaccine distribution globally, and we have the luxury of choosing which one is the best to use,” adds Tleyjeh. Unfortunately, he says “we are far from this point.” Chun agrees, adding that the ultimate goal remains “to get these vaccines to as many people as possible” as “both of these vaccines are highly effective.”
But Sette and Venkatakrishnan say the comparison is worth it. They agree that now is a unique moment in history, where many vaccines are available at the same time, and real data on humans is and will be generated to test how effective and durable each option is.
In the case of the Pfizer/BioNTech versus Moderna, given both are similarly designed, researchers can specifically compare the few most evident differences between them: the dosage, intervals between shots, and nanoparticle composition. If any of those is “helping one vaccine perform better over the other,” says Venkatakrishnan, perhaps other vaccines can be improved. “So there are things that we can learn from one protocol compared to the other,” he concludes.
Just as the playful rivalries in Twitter or TikTok are ultimately meant to celebrate vaccination, research comparing the different vaccines against SARS-CoV-2 is aimed at optimizing the vaccines rather than supporting a particular brand. It’s not #TeamModerna or #TeamPfizer—everyone is just focused on defeating COVID-19.
Clarification (September 24): The article was updated to clarify AJ Venkatakrishnan’s title.