On Monday, news outlets and scientists alike were celebrating. That morning, vaccine manufacturers Pfizer and BioNTech released the results of an interim data analysis of their COVID-19 vaccine that revealed that the vaccine was 90 percent protective against symptomatic COVID-19. But while advances toward a safe and effective vaccine are unquestionably welcome after nearly a year of the COVID-19 pandemic upending life as we know it, there’s reason for some caution. This interim analysis is preliminary, and we need more data from the ongoing clinical trial—so it’s still going to be a long time before you can even think about not wearing a mask.
In Phase 3 clinical trials, vaccine safety and efficacy are determined by analyzing “events”—in this case, confirmed cases of symptomatic COVID-19. This interim analysis, which was conducted by an independent scientific panel overseeing the trial, looked at 94 combined events in the control (placebo) and vaccinated groups and concluded that the vaccine protected 90 percent of those who received it. One reason why this is so exciting is that it exceeded expectations—initial hopes were that vaccine efficacy would be around 70 percent. However, it’s important to note that the 94 events meeting the criteria for inclusion in the interim analysis are a fraction of the nearly 39,000 trial participants that have already completed the two-dose regimen. It’s possible that there were other COVID-19 cases that, for some reason, were not included in that analysis. Whether the vaccine will be 90 percent effective when additional events are included remains to be seen.
In addition, the analysis included no information about the demographic breakdown of trial participants or about disease severity. That is particularly important to consider when evaluating a vaccine for COVID-19, which disproportionately causes severe disease in older people or people with certain very common comorbidities, such as heart disease, diabetes, or asthma. We already know that some vaccines are less effective in older people. Influenza vaccines, for example, are formulated differently for people over 65 to ensure that they can elicit robust, protective immune responses. For flu shots, this is accomplished by either giving a higher dose of the vaccine or formulating it with an adjuvant, an additive that enhances immune responses to a vaccine. If a vaccine directed against SARS-CoV-2 elicits similarly blunted immune responses in older people, it may need to be reformulated to ensure that it can protect people who are at higher risk of severe COVID-19. This data is likely forthcoming, and will certainly be included in an application to the Food and Drug Administration for approval.
Another question that the information we have so far can’t answer is whether, in addition to keeping you from getting sick, the vaccine prevents you from transmitting the virus to others. Undoubtedly, reducing disease severity would be a huge public health achievement, given the tremendous burden on health care systems that we are seeing now as cases and hospitalizations rise. However, if vaccinated individuals can still be infected and potentially transmit the virus to other, nonvaccinated individuals, it will ultimately make the pandemic more difficult to control through immunization. It may even increase transmission if asymptomatic vaccinated individuals, unaware they are infected, shed sufficient virus to transmit to others. The effect of mild or asymptomatic disease in vaccinated individuals on long-term outcomes is also unknown but must be studied going forward given the increasing appreciation for “long-haulers,” who suffer significant disease long after the initial infection was cleared, including in some people with mild COVID-19.
This is not an issue that is unique to the Pfizer/BioNTech vaccine. Most of the vaccine candidates currently in Phase 3 trials are being evaluated for their ability to protect against symptomatic COVID-19. In part this makes trial design easier—events are more likely to be detected in symptomatic trial participants, and reducing virulence and pathology and thus disease severity is critical to relieving overwhelmed hospital systems. Furthermore, vaccines against respiratory pathogens often do not induce sterilizing immunity, particularly when delivered intramuscularly through a shot. Based on preclinical studies in nonhuman primates as well as Phase 1 and 2 clinical trials, most of the leading vaccine candidates, including Pfizer’s, produce high levels of IgG antibodies, the type that are most often associated with neutralization and would block productive infection, resulting in little to no virus shedding in vaccinated individuals.
Preclinical challenge studies in monkeys support this. In these studies, rhesus macaques are vaccinated and then “challenged” by being deliberately infected with SARS-CoV-2. Then nasal swabs and fluid from a wash of the full respiratory tract are tested for SARS-CoV-2 subgenomic RNA, which indicates replicating virus. The vast majority of vaccines tested in challenge studies showed some subgenomic RNA in nasal swabs and the respiratory tract fluid, indicating that vaccines did not provide completely sterilizing immunity. Again, however, this does not mean these vaccines do not work—they all showed significant reductions in disease pathology, and there was less subgenomic RNA in fewer vaccinated animals than the control unvaccinated groups. Vaccinated individuals may be less likely to shed sufficient virus to transmit, but this may not be absolute.
The Pfizer vaccine’s interim results are both a monumental step forward and a reason to exercise caution and manage our expectations. On one hand, the urgent need for a COVID-19 vaccine has advanced new technologies that will serve us well in preparing for future pandemics. On the other, we need to manage our expectations about what these interim results mean. A vaccine, even with promising preliminary results, is not an instantaneous cure for the pandemic. Even if data from the trials suggests that the Pfizer vaccine is extraordinary, it will not be ready for FDA approval until the end of November at the earliest to allow for collection of critical safety data, and from there, it will take months to distribute the vaccine widely. And mRNA vaccines like the Pfizer and Moderna vaccines require ultracold freezer storage (the Pfizer vaccine has to be kept at -80 degrees Celsius), creating an entirely new logistical problem.
Even in the best circumstances, it will take months to go from encouraging clinical trial data to getting a vaccine on demand at your local pharmacy or from your primary care provider. We all have to remain vigilant with other measures to reduce community transmission, such as risk reduction (masks, social distancing, good ventilation, avoiding crowds, etc.) and increasing testing capacity in the meantime.
The good news, however, is that all the preliminary data, including this interim analysis, suggests that the vaccine candidates in the pipeline are performing very well relative to what was expected. Even though the first vaccines to come to market may not be perfect, they will be a powerful tool in the fight to control the pandemic for good. There will be more interim analyses in the near future and we will likely have multiple vaccines in the pandemic-fighting toolbox. Moderna recently announced it had reached the event threshold that would trigger an interim analysis by its own data safety monitoring board, and other candidates in late-stage clinical trials will likely follow. Hope is on the horizon. We just still have a long way to travel.